Croft Lab

Croft Lab

"The whole appeal of this Institute is that it’s small, very focused, and you have the potential for really good interactions with experts in related but diverse fields of immunology. That’s why it does well and functions well." — Michael Croft, Ph.D. // Division Head and Professor
Division of Immune Regulation

Overview

Michael Croft, Ph.D., and his team focus on a number of molecules that are members of the tumor necrosis factor (TNF) and tumor necrosis factor receptor (TNFR) family, a group of proteins believed to play important roles in the ability of the immune system to guard the body against harmful microorganisms. The TNFR molecules studied by Dr. Croft and his laboratory are expressed on T lymphocytes and other cells of the immune system and emerging evidence is suggesting they are crucial for the effective function of these cells in many types of immune response.

Currently, four classes of drugs have been approved for clinical use that target molecules in the TNF and TNFR protein families. Dr. Croft’s laboratory is investigating the roles of other related molecules in several diseases, including asthma, atopic dermatitis, and scleroderma to determine if they could be targets for therapeutic intervention to suppress disease symptoms. Another line of research is investigating whether substances that can signal T cells and other immune cells through TNFR family proteins can be used to increase natural immune responses. This is particularly important for vaccination against viruses and diseases such as cancer, in which T cells do not function strongly enough or fast enough to combat the growth of the virus or growth of the tumor cells.

Dr. Croft is the primary inventor on a number of patents directed at autoimmune/inflammatory disease therapy targeting the TNF family and he has consulted for many major pharmaceutical firms. Dr. Croft is a Fellow of the American Asthma Foundation (formerly the Sandler Asthma Foundation). His research on OX40/OX40L interactions controlling the generation and activity of Th2 cells is cited by the Foundation as one of their major breakthroughs, and led to clinical trials of antagonists of OX40L in asthma.

Dr. Croft has been a member of the American Association of Immunologists (AAI) for many years and has served on the Nominating Committee that elects the members of the various committees of the AAI including the Council Members and President. He also programmed the Annual Meeting of the AAI for a period of 5 years serving as Block Symposia Program Chair; has been chair of several major symposia at the AAI annual meeting; and has been honored as invited speaker in the AAI President’s Symposium on two separate occasions. Dr. Croft has also been teaching faculty on several occasions on both the AAI advanced and introductory immunology courses. Dr. Croft has furthermore been on the Scientific Advisory and programming committee of the International TNF superfamily conference on several occasions. He has served on a number of NIH Study sections as permanent member or ad-hoc. He has served as Associate Editor of the Journal of Immunology and Frontiers in Immunology, and is a member of Faculty 1000 prime.

Croft Lab

Publications

J Immunol

Aging converts innate B1a cells into potent CD8+ T cell inducers

2016-04
Lee-Chang C, Bodogai M, Moritoh K, Chen Z, Wersto R, Sen R, Young HA, Croft M, Ferrucci L, Biragyn A
J Allergy Clin Immunol

Segmental allergan challenge increases levels of airway follistatin-like 1 in patients with asthma

2016-03
Miller M, Esnault S, Kurten RC, Kelly EA, Beppu A, Das S, Rosenthal P, Ramsdell J, Croft M, Zuraw B, Jarjour N, Hamid…
Pharmacol Res

The control of tissue fibrosis by the inflammatory molecule LIGHT (TNF superfamily member 14)

2016-02
Herro R, Croft M
J Allergy Clin Immunol

Rhinovirus infection interferes with induction of tolerance to aeroantigens through OX40 ligand, thymic stromal lymphopoietin, and IL-33

2016-01
Mehta AK, Duan W, Doemer AM, Traves SL, Broide DH, Proud D, Zuraw BL, Croft M
Journal of Immunology

Fstl1 promotes asthmatic airway remodeling by inducing oncostatin M

2015-10
Miller M, Beppu A, Rosenthal P, Pham A, Das S, Karta M, Song DJ, Vuong C, Doherty T, Croft M, Zuraw B, Shang X, Gao X,…
Journal of Immunology

The TNF family molecules LIGHT and Lymphotoxin αβ induce a distinct steriod-resistant inflammatory phenotype in human lung epithelial cells

2015-09
da Silva Antunes R, Madge L, Soroosh P, Tocker J, Croft M
Journal of Allergy and Clinical Immunology

Tumor necrosis factor superfmaily 14 (LIGHT) controls thymic stromal lymphopoietin to drive pulmonary fibrosis

2015-09
Herro R, Da Silva Antunes R, Aguilera AR, Tamada K, Croft M
Journal of Investigative Dermatology

The tumor necrosis factor superfamily molecule LIGHT promotes keratinocyte activity and skin fibrosis

2015-08
Herro R, Da Silva Antunes R, Aguilera AR, Tamada K, Croft M
Journal of Immunology

OX40- and CD27-mediated costimulation synergizes with anti-PD-L1 blockade by forcing exhausted CD8+ T cells to exit quiescence

2015-01
Buchan SL, Manzo T, Flutter B, Rogel A, Edwards N, Zhang L, Sivakumaran S, Ghorashian S, Carpenter B, Bennett CL,…
Journal of Immunology

4-1BB ligand signaling to T cells limits T cell activation

2015-01
Eun SY, Lee SW, Xu Y, Croft M
Annals of the American Thoracic Society

Control of regulatory T cells and airway tolerance by lung macrophages and dendritic cells

2014-12
Duan W, Croft M
Blood

Accumulation of 4-1BBL+ B cells in the elderly induces the generation of granzyme-B+ CD8+ T cells with potential antitumor activity

2014-08
Lee-Chang C, Bodogai M, Moritoh K, Olkhanud PB, Chan AC, Croft M, Mattison JA, Holst PJ, Gress RE, Ferrucci L, Hakim F,…
Seminars in Immunology

The TNF family in T cell differenciation and function - unanswered questions and futher directions

2014-06
Croft M
Journal of Experimental Medicine

Galectin-9 controls the therapeutic activity of 4-1BB-targeting antibodies

2014-06
Madireddi S, Eun SY, Lee SW, Nemcovicova I, Mehta AK, Zajonc DM, Nishi N, Niki T, Hirashima M, Croft M
Nature Immunology

The adaptor TRAF5 limits the differentiation of inflammatory CD4(+) T cells by antagonizing signaling via the receptor for IL-6

2014-05
Nagashima H, Okuyama Y, Asao A, Kawabe T, Yamaki S, Nakano H, Croft M, Ishii N, So T
Journal of Immunology

Exogenous OX40 stimulation during lymphocytic choriomeningitis virus infection impairs follicular Th cell differentiation and diverts DC4 T cells into the effector lineage by upregulating blimp-1

2013-11
Boettler T, Choi YS, Salek-Ardakani S, Cheng Y, Moeckel F, Croft M, Crotty S, von Herrath M
PLoS One

CD8 T cell memory to a viral pathogen requires trans cosignaling between HVEM and BTLA

2013-10
Flynn R, Hutchinson T, Murphy KM, Ware CF, Croft M, Salek-Ardakani S
Science Signaling

The TNF family member 4-1BBL sustains inflammation by interacting with TLR signaling components during late-phase activation

2013-10
Ma J, Bang BR, Lu J, Eun SY, Otsuka M, Croft M, Tobias P, Han J, Takeuchi O, Akira S, Karin M, Yagita H, Kang YJ
Journal of Experimental Medicine

Inherited human OX40 dificiency underlying classic Kaposi sarcoma of childhood

2013-08
Byun M, Ma CS, Akçay A, Pedergnana V, Palendira U, Myoung J, Avery DT, Liu Y, Abhayankar A, Lorenzo L, Schmidt M, Lim…
PLoS One

Regulation of A1 by OX40 contributes to CD8(+) T cell survival and anti-tumor activity

2013-08
Lei F, Song J, Haque R, Haque M, Xiong X, Fang D, Croft M, Song J
Journal of Allergy and Clinical Immunology

Lung type 2 innate lymphoid cells express cysteinyl leukotriene receptor 1, which regulates TH2 cytokine production

2013-07
Doherty TA, Khorram N, Lund S, Mehta AK, Croft M, Broide DH
European Journal of Immunology

Transgenic expression of survivin compensates for OX40-deficiency in driving Th2 development and allergic inflammation

2013-07
Lei F, Song J, Haque R, Xiong X, Fang D, Lens SM, Croft M, Song J
Nature Immunology

Intrahepatic meyloid-cell aggregates enable local proliferation of CD8(+) T cells and successful immunotherapy against chronic viral liver infection

2013-06
Huang LR, Wohlleber D, Reisinger F, Jenne CN, Cheng RL, Abdullah Z, Schildberg FA, Odenthal M, Dienes HP, van Rooijen…
Frontiers in Immunology

Regulation of PI-3-kinase and akt signaling in T lymphocytes and other cells by TNFR family molecules

2013-06
So T, Croft M
Proceedings of the National Academy of Sciences of the United States of America

Vaccina virus F1L protein promotes virulence by inhibiting inflammasome activation

2013-05
Gerlic M, Faustin B, Postigo A, Yu EC, Proell M, Gombosuren N, Krajewska M, Flynn R, Croft M, Way M, Satterthwair A,…
PLoS One

Regulation of immune responsiveness in vivo by disrupting an early T-cell signaling event using a cell-permeable peptide

2013-05
Guimond DM, Cam NR, Hirve N, Duan W, Lambris DJ, Croft M, Tsoukas CD
Journal of Experimental Medicine

Lung-resident tissue macrophages generate Foxp3+ regulatory T cells an dpromote airway tolerance

2013-04
Soroosh P, Doherty TA, Duan W, Mehta AK, Choi H, Adams YF, Mikulski Z, Khorram N, Rosenthal P, Broide DH, Croft M
Nature Reviews Drug Discovery

Clinical targeting of the TNF and TNFR superfamilies

2013-02
Croft M, Benedict CA, Ware CF
Cellular Signalling

Novel transmembrane protein 126A (TMEM126A) couples with CD137L reverse signals in myeloid cells

2012-12
Bae JS, Choi JK, Moon JH, Kim EC, Croft M, Lee HW
American Journal of Physiology-Lung Cellular and Molecular Physiology

STAT6 regulates natural helper cells proliferation during lung inflammation initiated by alternaria

2012-10
Doherty TA, Khorram N, Chang JE, Kim HK, Rosenthal P, Croft M, Brolde DH
PLoS Pathogens

OX40 facilitates control of a persistent virus infection

2012-09
Boettler T, Moeckel F, Cheng Y, Heeg M, Salek-Ardakani S, Crotty S, Croft M, von Herrath MG
Journal of Immunology

Cutting edge: 4-1BB controls regulatory activity in dendritic cells through promoting optimal expression of retinal dehydrogenase

2012-09
Lee SW, Park Y, Eun SY, Madireddi S, Cheroutre H, Croft M
Journal of Immunology

CD8 T cells are essential for recovery from a respiratory vaccinia virus infection

2012-09
Goulding J, Bogye R, Tahiliani V, Croft M, Salek-Ardakani S
Diabetes

Following the fate of one insulin-reactive CD4 T cell: conversion into teffs and tregs in the periphery controls deiabetes in NOD mice

2012-05
Fousteri G, Jasinski J, Dave A, Nakayama M, Pagni P, Lambolez F, Juntti T, Sarikonda G, Cheng Y, Croft M, Cheroutre H,…
Trends in Immunology

TNF superfamily in inflammatory disease: translating basic insights

2012-03
Croft M, Duan W, Choi H, Eun SY, Madireddi S, Mehta A
Journal of Immunology

Alternaria induces STAT6-dependent acute airway eosinophilia and epithelial FIZZ1 expression that promotes airway fibrosis and epithelial thicknessAlternaria induces STAT6-dependent acute airway eosinophilia and epithelial FIZZ1 expression that promotes airway fibrosis and epithelial thicknessAlternaria induces STAT6-dependent acute airway eosinophilia and epithelial FIZZ1 expression that promotes airway fibrosis and epithelial thickness

2012-03
Doherty TA, Khorram N, Sugimoto K, Sheppard D, Rosenthal P, Cho JY, Pham A, Miller M, Croft M, Broide DH
Immunology Letters

Dispensable role for 4-1BB and 4-1BBL in development of vaccinia virus-specific CD8 T cells

2012-01
Zhao Y, Croft M
Journal of Autoimmunity

Antigen-specific prevention of type 1 diabetes in NOD mice is ameliorated by OX40 agonist treatment

2011-12
Bresson D, Fousteri G, Manenkova Y, Croft M, von Herrath M
Journal of Immunology

Inductible CD4+LAP+Foxp3- regulatory T cells suppress allergic inflammation

2011-12
Duan W, So T, Mehta AK, Choi H, Croft M
Viral Immunology

Preferential replication of vaccinia virus in the ovaries is independent of immune regulation through IL-10 and TGF-β

2011-10
Zhao Y, Adams YF, Croft M
Journal of Virology

Targeting OX40 promotes lung resident memory CD8 T cell populations that protect against respiratory poxvirus infection

2011-09
Salek-Ardakani S, Moutaftsi M, Sette A, Croft M
Proceedings of the National Academy of Sciences of the United States of America

Nucleotide oligomerization domain-containing proteins instruct T cell helper type 2 immunity through stromal activation

2011-09
Magalhaes JG, Rubino SJ, Travassos LH, Le Bourhis L, Duan W, Sellge G, Geddes K, Reardon C, Lechmann M, Carneiro LA,…
Immunotherapy

Therapeutic potential of targeting TNF/TNFR family members in asthema

2011-08
Doherty TA, Croft M
Journal of Immunology

Nitric oxide modulates TGF-{beta}-directive signals to supporess foxp3+ regulatory T cell differentiation and potentiate Th1 development

2011-06
Lee SW, Choi H, Eun SY, Fukuyama S, Croft M
Journal of Autoimmunity

Nasal cardiac myosin peptide treatment and OX40 blockade protect mice from acute and chronic virally-induced myocarditis

2011-05
Fousteri G, Dave A, Morin B, Omid S, Croft M, von Herrath MG
Journal of Immunology

B cell-specific expression of b7-2 is required for follicular th cell function in response to vaccinia virus

2011-05
Salek-Ardakani S, Choi YS, Rafii-El-Idrissi Benhnia M, Flynn R, Arens R, Shoenberger S, Crotty S, Croft M,…
Nature Medicine

The tumor necrosis factor family member LIGHT is a target for asthmatic airway remodeling

2011-05
Doherty TA, Soroosh P, Khorram N, Fukuyama S, Rosenthal P, Cho JY, Norris PS, Cho, H, Scheu S, Pfeffer K, Zuraw BL,…
Journal of Experimental Medicine

Herpesvirus entry mediator (TNFRSF14) regulates the persistence of T helper memory cell populations

2011-04
Soroosh P, Doherty TA, So T, Mehta AK, Khorram N, Norris PS, Scheu S, Pfeffer K, Ware C, Croft M
Journal of Immunology

OX40 complexes with phosphoinositide 3-kinase and protein kinase B (PKB) to augment TCR-dependent PKB signaling

2011-03
So T, Choi H, Croft M
Proceedings of the National Academy of Sciences of the United States of America

Antigen-independent signalosome of CARMA1, PKC(theta), and TNF receptor-associated factor 2 (TRAF2) determines NF-{kappa}B signaling in T cells

2011-02
So T, Soroosh P, Eun SY, Altman A, Croft M
Journal of Clinical Investigation

The TNFR family members OX40 and CD27 link viral virulence to protective T cell vaccines in mice

2011-01
Salek-Ardakani S, Flynn R, Arens R, Yagita H, Smith GL, Borst J, Schoenberger SP, Croft M
Front Immunol

How mouse macrophages sense what is going on

2016-06
Ley K, Pramod AB, Croft M, Ravichandran KS, Ting JP
Pharmacol Res

The control of tissue fibrosis by the inflammatory molecule LIGHT (TNF superfamily member 14)

2016-02
Herro R, Croft M
Frontiers in Immunology

Regulation of the PKCΘ-NF-KB axis in T lymphocytes by the tumor necrosis factor receptor family member OX40Regulation of the PKCΘ-NF-KB axis in T lymphocytes by the tumor necrosis factor receptor family member OX40

2016-08
So T, Croft M
Frontiers in Immunology

Targeting 4-1BB (CD137) to enhance CD8 T cell responses with poxviruses and viral antigens

2016-08
Zhao Y, Tahiliani V, Salek-Ardakani S, Croft M
European Journal of Immunology

Inhibition of 4-1BBL-regulated TLR response in macrophages ameliorates endotoxin-induced sepsis in mice

2016-02
Bang BR, Kim SJ, Yagita H, Croft M, Kang YJ

Principal Investigator

croft

Michael Croft, Ph.D.

Division Head and Professor

Dr. Croft is Head and Professor in the Division of Immune Regulation at LJI. Dr. Croft’s research focus is on the cellular regulation of immunity and tolerance, and how membrane bound and soluble stimulatory molecules control function of T cells and cells such as epithelial cells and fibroblasts that contribute to inflammatory and autoimmune disease.

Dr. Croft received a BSc in Biology from Brunel University in London, U.K, and a Ph.D. in Immunology from Sussex University in the U.K. In 1989 he moved to the Biology Department of the University of California, San Diego as a postdoctoral fellow. In 1996, Dr. Croft joined LJI as Assistant Professor, and was appointed as an Associate Professor in 2001. Dr. Croft was tenured in 2003, became Professor in 2005, and was appointed Head of the Division of Immune Regulation in 2010.

Lab Members

Taylor Doherty

Visiting Scientist

SAMSUNG CAMERA PICTURES

Donald Gracias

Postdoctoral Fellow

Biosketch:
I graduated from Goa University (Goa, India) with a Masters in Marine Biotechnology. I then obtained my Ph.D. degree in Microbiology and Immunology from the laboratory of Dr. Peter D. Katsikis at the Drexel University College of Medicine (Philadelphia, PA) in December 2012. After briefly working in the same laboratory as a postdoctoral researcher to wrap up my research studies, I joined the Croft Lab at the La Jolla Institute for Allergy and Immunology as a Postdoctoral fellow in July 2013.

Research Focus:
My research projects are focused on identifying the role of different TNFSF/TNFRSF superfamily members and other co-stimulatory molecules in regulating memory Th2 and regulatory T cells during allergic lung inflammation.

Career Goals:
My goal is to pursue a career in scientific research that focuses on identifying gene targets for treating/ameliorating immune-mediated inflammatory diseases.

RanaHerro

Rana Herro

Instructor

Biosketch:
I received my B.S. in Biochemistry from the University of Lebanon in Beirut, Lebanon, my M.S. in Microbiology from University of Rennes I, France, and my PhD in Genetics and Molecular Microbiology from the University of Paris XI in France. I began working as a postdoc in the Croft laboratory at the La Jolla Institute for Allergy and Immunology in 2012 and was promoted to the Instructor position in 2015.

Research Focus:
My research projects are focused on the roles of TNF family members linked to fibrotic disorders associated with scleroderma, atopic dermatitis, idiopathic pulmonary fibrosis and asthma.

Career Goals:
I plan to pursue an academic career in scientific research focused on signaling molecules involved in human disease.

Young Jun Kang

Visiting Scientist

AmitMehta

Amit Kumar Mehta, Ph.D.

Postdoctoral Fellow

Biosketch:
I graduated from DAVV University, India in 2003 with a M.S. degree in Biotechnology. I then obtained my Ph.D. Degree in Biotechnology from the University of Pune & CSIR-IGIB. I started working as a postdoc in the Croft laboratory at La Jolla Institute for Allergy and Immunology in Oct 2009.

Research Focus:
My research focuses on studying the role of different TNF super family members in controlling allergen induced asthma exacerbations and airway remodeling.

Career Goals:
Developing of novel immunotherapeutic strategies for the treatment of chronic allergic inflammation and airway remodeling.

BridgetRatitong

Bridget Ratitong, B.Sc.

Intern

Biosketch:
I graduated from UCSD in 2015 with a B.Sc. in Molecular Biology. I began working as an intern in the Croft laboratory at the La Jolla Institute for Allergy and Immunology in 2016.

Research Focus:
I assist post doctoral fellows in studying asthma in mouse models, phenotyping and genotyping rodents and assist in investigating some members of the TNF and TNFR superfamily and their effects in lung hypersensitivity and inflammation.

SAMSUNG CAMERA PICTURES

Daniel Sidler, M.D., Ph.D.

Postdoctoral Fellow

Biosketch:
I graduated from Medical School in 2006 and obtained my MD/PhD degree in biomedical research and Immunology in 2010 from the University of Bern (Switzerland). I completed my residency in Internal Medicine with Board Certification (Switzerland) in 2014 and am currently in training for specialisation in Nephrology/Transplantation. I began working as a postdoc in the Croft lab at the La Jolla Institute for Allergy and Immunology in November 2014.

Research Focus:
My research projects are focused on the roles of the TNF superfamily in general and TNFSF12 (TWEAK) in particular in chronic inflammatory disorders of the skin and kidney.

Career Goals:
I plan to pursue a dual career in clinical medicine and basic research focused on immunology, transplantation and autoimmunity.

XiaohongTang

Xiaohong Tang

Research Technician II

Biosketch:
I joined Dr. Grey’s lab in August 2002, and later went on to join Dr. Croft’s lab in June 2003, where I have remained since.

Research Focus:
I am highly trained in producing and purifying monoclonal antibodies from Hybridoma cells, performing ELISA assays, preparing primary cells from organs and analyzing cell populations using FlowJo Cytometry data analysis software, isolating genomic DNA from animal tissues, maintaining and screening numerous transgenic and knock out mice lines by PCR and FACS. I help postdoctoral fellows get their research up and running, assist in managing the lab budget and purchasing, maintain the lab equipment and ensure the lab is clean and organized. I also train new lab members.

Croft Lab

Research Projects

T cells

T cells are central to almost all immune responses. The CD4 subset is capable of directing B cell responses and humoral immunity, and can modulate the actions of many other cell types including CD8 T cells, dendritic cells, macrophages, eosinophils, and basophils. In addition, the CD8 subset primarily function as cytolytic killers for clearing pathogen-infected cells or for targeting tumors. Both subsets are also central causative agents of autoimmune disease. Further intricacies involve alternate subsets of T cells that express CD4 or CD8 that have regulatory or suppressive activity (Treg) and dampen or modulate the action of the effector-type T cells that have pathogenic or protective activity. T cells exert their actions in two ways, either through direct cell-cell contact which involves transmembrane proteins present on both the T cell and interacting cell, or by the secretion of soluble proteins termed cytokines which have receptors on many lymphoid and some non-lymphoid cell types. Infectious agents such as viruses are only cleared efficiently if a strong T cell response is elicited, and cancer cells can also be suppressed if the T cell response is optimized. In contrast, strong T cell responses directed against self-antigens and allergens can also be detrimental and lead to autoimmune disease such as MS, RA, scleroderma and diabetes, and inflammation such as characterized by allergies, asthma, and atopic dermatitis (eczema). The focus of the Croft laboratory is how both CD4 and CD8 T cell responses are regulated either intrinsically by direct signaling or extrinsically by regulatory T cell subsets, with particular emphasis on so-called costimulatory receptor-ligands that positively, and in some cases negatively, affect how a T cell responds and how well a T cell responds. Specifically, the lab focuses on several members of the TNF (tumor necrosis factor)/TNFR (tumor necrosis factor receptor) superfamily of proteins which are displayed as membrane molecules on the surface of T cells and antigen-presenting cells and certain non-lymphoid cells. Studies are being carried out to determine the functional effects that occur when these receptor-ligands interact; to determine how these proteins induce their activities at the molecular level and transmit signals to T cells; and to determine the significance of these proteins in several disease scenarios such as asthma, scleroderma, and atopic dermatitis. Because our current understanding suggests these molecules control many functional activities of T cells, and the effects might vary depending on the subset of T cell, they are therefore potential targets for either suppressing an immune response, or for promoting an immune response.

The TNF family molecules that are being studied most extensively are named OX40L, 4-1BBL, and LIGHT. Data from the laboratory shows that signals from these molecules through their receptors control the activities and long-term survival of T cells, as well as affecting the activities of other cell types including dendritic cells, macrophages, and epithelial cells. The laboratory has investigated the roles of these molecules in inflammatory and autoimmune diseases to determine if modulating their activity alters the immune response and may be useful for therapeutic intervention. Other research is investigating whether agonist reagents that can signal various immune cells such as T cells, dendritic cells, or NK cells, through the TNF family receptors OX40, 4-1BB, HVEM, or LTβR can be used to increase natural immune responses to viruses or tumors that might lead to new strategies for vaccination.

Selected References

Croft, M. 2003. Costimulation of T cells by OX40, 4-1BB, and CD27. Cytokine and Growth Factor Reviews. 3-4:265.
Croft, M. 2003. Costimulatory members of the TNFR family: Keys to Effective T cell immunity. Nature Reviews Immunology. 3:609.
Croft, M. 2005. The evolving cross-talk between co-stimulatory and co-inhibitory receptors: HVEM-BTLA. Trends in Immunology. 26:292.
Salek-Ardakani, S., and Croft, M. 2006. Regulation of CD4 T cell memory by OX40 (CD134). Vaccine. 24:872.
So, T., Lee, S-W., and Croft, M. 2006. TNF/TNFR family members that positively regulate immunity. International Journal of Hematology. 83:1.
So, T., Lee, S-W., and Croft, M. 2008. Immune regulation and control of regulatory T cells by OX40 and 4-1BB. Cytokine and Growth Factor Reviews. 19:253.
Lee, S-W., and Croft, M. 2009. 4-1BB as a therapeutic target for human disease. In Therapeutic Targets of the TNFR Superfamily. Advances in Experimental Medicine and Biology. 647:120.
Croft, M., T. So, W. Duan, and P. Soroosh. 2009. The significance of OX40 and OX40L to T-cell biology and immune disease. Immunological Reviews. 229:173.

Croft, M. 2009. The role of TNF superfamily members in T-cell function and diseases. Nature Reviews Immunology. 9:271.
Croft, M. 2010. Control of immunity by the TNFR-related molecule OX40 (CD134). Annual Reviews in Immunology. 28:57.
Salek-Ardakani, S., and Croft, M. 2010. TNFR/TNF family members in antiviral CD8 T cell immunity. Journal of Interferon & Cytokine Research. 30:205.
Doherty, T.A., and Croft, M. 2011. The therapeutic potential of targeting TNF/TNFR family members in asthma. Immunotherapy. 3:919.
Croft, M., Duan, W., Choi, H., Eun, S-Y., Madireddi, S., and Mehta, A. 2012. TNF superfamily in inflammatory disease: translating basic insights. Trends in Immunology. 33:144.
So, T., and Croft, M. 2012. Regulation of the PKCθ-NF-κB axis in T lymphocytes by the tumor necrosis factor receptor family member OX40. Frontiers in Immunology. 3:133.
Croft, M., Benedict, C.A., and Ware, C.F. 2013. Clinical targeting of the TNF and TNFR superfamilies. Nature Reviews Drug Discovery. 12:147.
So, T., and Croft, M. 2013. Regulation of PI-3-Kinase and Akt signaling in T lymphocytes and other cells by TNFR family molecules. Frontiers in Immunology. 4:139. PMCID: PMC3675380
Croft, M. 2014. The TNF family in T cell differentiation and function – Unanswered questions and future directions. Seminars in Immunology. 26:183.

T Cell Response

The response of T cells can be controlled by costimulatory molecules present on APC that interact with co-receptors present on the T cell. The ligand-receptor pairs which may determine the fate of the T cell include B7:CD28, ICAM-1:LFA-1, 4-1BBL:4-1BB, OX40L:OX40, and CD40:CD40L (Croft and Dubey, 1997, Crit Rev Immunol). The initial activation of a naïve T cell is controlled by recognition of peptide/MHC complexes and does not appear to require any other interactions. This was shown in studies where activation of naïve T cells was analyzed with peptide presented on surrogate fibroblast APCs that either expressed B7 and/or ICAM, or were deficient in these molecules. Blastogenesis, entry into cell cycle, and upregulation of many surface molecules (e.g. CD25, CD69) occur equivalently regardless of the presence of costimulation, and expression of only two molecules, namely membrane-bound CD40L and secreted IL-2, critically require costimulatory signals (Jaiswal, 1996, Int Immunol; Croft, 1997, J Immunol). Functionally, T cells stimulated by antigen but without costimulatory signals, are able to proliferate and expand in numbers, but only transiently, with proliferation being very short-lived and few T cells being able to survive over time (Rogers, 1998, J Immunol). Additionally, the small number of T cells that are generated are unresponsive to antigen, entering into a state of tolerance (Croft, 1997, J Immunol). Our older data had shown that the molecules B7 and ICAM could costimulate naïve T cell activation when expressed in isolation, but an efficient response, including high levels of CD40L, IL-2, and short-term proliferation, resulted only when both B7 and ICAM were able to signal through CD28 and LFA-1 at the same time (Dubey, 1995, J Immunol; Jaiswal, 1996, Int Immunol; Rogers, 1998, J Immunol). Collectively, this demonstrates that the T cell membrane proteins CD28, LFA-1, and CD40L and the secreted protein, IL-2, are crucial molecules that may determine the short-term fate of T cells.

The hallmark of an effective T cell response is the formation of a stable long-lived population of cells that mediate immune memory. Although the interactions of ICAM/LFA, CD40/CD40L, and B7/CD28 explain how the early T cell response is driven, these interactions are not sufficient for promoting effective memory. Our present studies are focusing on the molecular interactions which prevent excessive T cell death after the initial period of clonal expansion and which are essential for promoting late T cell division and providing long-term survival signals. It is likely that again these events are mediated by a number of different cell bound molecules. Candidates are several members of the tumor necrosis factor receptor (TNFR) family, and our laboratory is focusing on a number of these molecules.

Introduction to OX40

OX40 (CD134) is a 50 kD type I transmembrane glycoprotein in the TNFR superfamily, containing 3 full cysteine rich domains, and a relatively short cytoplasmic tail, and although a monomer it signals as a trimer when bound to OX40L, its known ligand in the TNF family. OX40 is not constitutively expressed on naïve CD4 or CD8 T cells but is induced after antigen recognition. High-level expression can result under inflammatory and tolerogenic conditions in vivo, and OX40 can be maintained for a number of days under adjuvant-induced inflammatory conditions. However, OX40 is constitutively present on the surface of Foxp3+ nTreg, and constitutive or inducible on Foxp3+ iTreg. Similarly, OX40L is inducible and has been found on activated/mature APC such as dendritic cells, B cells, and macrophages. OX40 is downregulated after the effector phase of T cell responses, but might be retained at low levels on subpopulations of memory T cells as well as Treg. It is rapidly re-expressed at high levels on effector/memory T cells once antigen is seen again. Our early studies of OX40 in vivo used knockout animals made deficient in OX40 or blocking studies with antibody preventing OX40L binding to OX40. These demonstrated that both primary CD4 and CD8 T cell responses and development of memory to protein antigen in adjuvants (e.g. CFA, alum), or to several viruses, or to a range of tumors are strongly controlled by OX40. The poor responses were largely due to weak expansion of naïve T cells, which translated to fewer T cells surviving to become memory. Our studies in OX40-deficient animals have additionally been supported by experiments using stimulatory antibodies which promote an increase in the number of primary effector and memory T cells that develop, again suggesting that a major role of OX40 signals is to regulate effector T cell division and expansion and survival, and suppress apoptosis. We have identified several molecular targets such as Bcl-xL, Bcl-2, and survivin, along with upstream signaling intermediates such as PI-3-kinase, Akt, and the canonical and non-canonical NF-κB pathways that control the activities of OX40. Several studies have also suggested that OX40 signals can directly prevent suppressive activity of nTreg and can inhibit the induction of iTreg which further aid the clonal expansion and differentiation of effector T cells. Studies in experimental animal models have now not only stressed the importance of OX40 and OX40L for autoimmune and inflammatory disease manifestations, but shown that inhibiting this interaction can be useful therapeutically. For example, inhibiting OX40/OX40L interactions can abrogate Th2 or Th1/Th17-induced pathologies in experimental leishmaniasis, EAE, graft-versus-host disease, transplantation, inflammatory bowel disease, asthma, and collagen-induced arthritis. These studies have highlighted the broad reaching control of T cell responses by OX40 and OX40L, and promoted this interaction to the forefront of potential therapies aimed at dampening T cell driven immune diseases. Agonist reagents that stimulate OX40 also have great potential therapeutically for vaccination, as shown by a number of studies in tumor models or of responses to viruses where the immune response can be boosted dramatically to aid protection. The lab is currently focusing on how OX40 drives responses to allergens that link to asthmatic and allergic disease, and how OX40 synergizes with other TNFR family or non-TNFR family molecules to control allergen-reactive T cells. Understanding this is likely to lead to combination therapeutic approaches for allergic disease.

Selected References

Bansal-Pakala, P., Jember, A. G-H, and Croft, M. 2001. Signaling through OX40 (CD134) breaks peripheral T cell tolerance. Nature Medicine. 7:907.
Rogers, P.R., Song, J., Gramaglia, I., Killeen, N., and Croft, M. 2001. OX40 promotes Bcl-xL and Bcl-2 expression and is essential for long-term survival of CD4 T cells. Immunity. 15:445.
Salek-Ardakani, S., Song, J., Halteman, B.S., Jember, A. G-H., Akiba, H., Yagita, H., and Croft, M. 2003. OX40 (CD134) controls memory T helper 2 cells that drive lung inflammation. Journal of Experimental Medicine. 198:315
Song, J., Cheng, M., Tang, X., and Croft, M. 2005. Sustained survivin expression from OX40 costimulatory signals drives T cell clonal expansion. Immunity 22:621.
So, T., and Croft, M. 2007. Cutting Edge: OX40 inhibits TGF-β and antigen-driven conversion of naïve CD4 T cells into CD25+Foxp3+ T cells. Journal of Immunology. 179:1427.
So, T., Soroosh, P., Eun, S-Y., Altman, A., and Croft, M. 2011. An antigen-independent signalosome of CARMA1, PKCθ, and TRAF2 determines NF-κB signaling in T cells. Proceedings of the National Academy of Sciences. 108:2903.
Salek-Ardakani, S., Flynn, R., Arens, R., Yagita, H., Smith, G.L., Borst, J., Schoenberger, S.P., and Croft, M. 2011. The TNFR family members OX40 and CD27 link viral virulence to protective T cell vaccines in mice. Journal of Clinical Investigation. 121:296.
Boettler, T., Moeckel, F., Cheng, Y., Heeg, M., Salek-Ardakani, S., Crotty, S., Croft, M., and Von Herrath, M. 2012. OX40 facilitates control of a persistent virus infection. PLoS Pathogens. 8:e1002913.
Lei, F., Song, J., Haque, R., Haque, M., Xiong, X., Fang, D., Croft, M., and Song, J. 2013. Regulation of A1 by OX40 contributes to CD8+ T cell survival and anti-tumor activity. PLoS One. 8:e70635.
Mehta, A.K., Duan, W., Doerner, A.M., Traves, S.L., Broide, D.H., Proud, D., Zuraw, B.L., and Croft, M. 2015. Rhinovirus infection interferes with the induction of tolerance to aeroantigens through OX40 ligand, thymic stromal lymphopoietin, and IL-33. Journal of Allergy and Clinical Immunology 10.1016/j.jaci.2015.05.007

Introduction to 4-1BB

4-1BB (CD137) is a 30 kD type I glycoprotein and again a typical transmembrane receptor in the TNFR superfamily, containing 4 full cysteine rich domains, and a relatively short cytoplasmic tail, and also signals as a trimer when bound to 4-1BBL, its known ligand in the TNF family. Although 4-1BB was originally thought to be only expressed after activation of conventional CD4 and CD8 T cells, it is constitutive (NK cells) or induced (NKT cells, dendritic cells) on other cell types. Similarly, 4-1BB is present or induced on iTreg and nTreg. 4-1BBL was largely thought to be on APC that have been activated for several days, such as dendritic cells, B cells, and macrophages although again it is clear that 4-1BBL is now more ubiquitous as it has been visualized to be induced on diverse cell types such as mast cells, osteoclasts, smooth muscle, and stem cells. Initial studies demonstrated that ligation of 4-1BB on T cells could deliver costimulatory signals resulting in either increased proliferation or enhanced cytokine secretion and also control clonal expansion and differentiation of effector and memory T cells. 4-1BB can furthermore promote expression of survival proteins in T cells, although its activities in other cell types appear to vary depending on the cell and the primary function. Many studies in tumor models have forcibly provided 4-1BB signals, injecting either agonist antibodies to 4-1BB, or transfecting 4-1BBL into the tumor cells, also highlighting the stimulatory capability of 4-1BB in driving suppression of tumor growth largely through augmenting CTL and NK responses. The in vivo role of 4-1BBL/4-1BB has been addressed in various infectious model systems with bacteria or viruses where in general the molecules control memory development in the CD4 or CD8 T cell compartment, although the requirement for these molecules varies depending on the pathogen. Other data with either gene-deficient animals or with agonist reagents to 4-1BB have highlighted another aspect of biology in that a suppressive activity has been observed, for example, where stimulating 4-1BB in autoimmune models of MS or rheumatoid arthritis inhibits disease progression and pathology. Gene-deficient mice also exhibit signs of spontaneous inflammatory disease, leading to the hypothesis that 4-1BB/4-1BBL interactions also play major regulatory roles which might be manifest at the level of Treg or regulatory APC that promote Treg activity. The lab is currently focusing on novel binding partners for 4-1BB, such as Galectin-9, that control its functional activity, and how suppressive signals from 4-1BB or 4-1BBL downregulate T cell and APC activities.

Selected References

Lee, S-W., Park, Y., So, T., Kwon, B.S., Cheroutre, H., Mittler, R.S., and Croft, M. 2008. Identification of regulatory functions for 4-1BB and 4-1BBL in myelopoiesis and the development of dendritic cells. Nature Immunology. 9:917.
Lee, S-W., Salek-Ardakani, S., Mittler, R.S., and Croft, M. 2009. Hyper-costimulation through 4-1BB distorts homeostasis of immune cells. Journal of Immunology. 182:6753.
Lee, S-W., Park, Y., Eun, S-Y., Cheroutre, H., Madireddi, S., and Croft, M. 2012. Cutting Edge: 4-1BB controls regulatory activity in dendritic cells through promoting optimal expression of retinal dehydrogenase. Journal of Immunology. 189:2697.
Zhao, Y., Tahiliani, V., Salek-Ardakani, S., and Croft, M. 2012. Targeting 4-1BB (CD137) to enhance CD8 T cell responses with poxviruses and viral antigens. Frontiers in Immunology. 3:332.
Madireddi, S., Eun, S-Y., Lee, S-W., Nemcovicova, I., Mehta, A.K., Zajonc, D.M., Nishi, N., Niki, T., Hirashima, M., and Croft, M. 2014. Galectin-9 controls the therapeutic activity of 4-1BB-targeting antibodies. Journal of Experimental Medicine. 211:1433.
Eun, S-Y., Lee, S-W., Xu, Y., and Croft, M. 2015. 4-1BB ligand signaling to T cells limits T cell activation. Journal of Immunology. 194:134

Introduction to LIGHT

LIGHT is another member of the TNF family that can be induced on multiple cell types including T cells and dendritic cells. LIGHT can bind LTβR, a TNFR family molecule constitutively expressed on stromal cells, dendritic cells, macrophages, and some epithelial cells. LIGHT can also bind a separate receptor in the TNFR family named HVEM. Adding further complexity, HVEM can also bind the inhibitory molecules BTLA and CD160. LIGHT is largely regarded as a pro-inflammatory molecule that might regulate multiple aspects of the immune response including controlling T cell functionality. The most compelling argument for an inflammatory role has come from studies of transgenic mice that over express LIGHT in the T cell lineage. These mice develop spontaneous autoimmune-like signs, including splenomegaly, accumulation of activated T cells and autoantibodies, and pathological features of inflammation in the intestine. Furthermore, LIGHT as a transgene can promote enhanced immune inflammation, such as seen in atherosclerosis and Crohn's disease, when animals or cells derived from them are used under conditions conducive for such diseases. Blocking the interactions of LIGHT with HVEM and/or LTβR and/or BTLA result in decreased inflammation in models of GVHD, transplantation, MS, RA, asthma, IPF, and scleroderma. The role of these molecules in driving disease pathology might vary, with described activities of HVEM signaling promoting T cell expansion or survival, analogous to certain activities of OX40 and 4-1BB, and other activities of HVEM or LTβR increasing the function of diverse cells such as stromal cells, dendritic cells, macrophages, eosinophils, epithelial cells and keratinocytes. The lab is currently focusing on the activity of LIGHT in regulating tissue remodeling and fibrosis that is characteristic of severe asthma, scleroderma, and atopic dermatitis.

Selected References

Soroosh, P., Doherty, T.A., So, T., Mehta, A.K., Khorram, N., Norris, P.S., Scheu, S., Pfeffer, K., Ware, C., and Croft, M. 2011. Herpesvirus entry mediator (TNFRSF14) regulates the persistence of T helper memory cell populations. Journal of Experimental Medicine. 208:797.
Doherty, T.A., Soroosh, P., Fukuyama, S., Cho, J.Y., Scheu, S., Pfeffer, K., Zuraw, B.L., Ware, C., Broide, D.H., and Croft, M. 2011. The TNF family member LIGHT is a target for asthmatic airway remodeling. Nature Medicine. 17:596.
Flynn, R., Goulding, J., Tahiliani, V., Murphy, K.M., Ware, C.F., Croft, M., and Salek-Ardakani, S. 2013. CD8 T cell memory to a viral pathogen requires trans cosignaling between HVEM and BTLA. PLoS One. 8:e77991.
Herro, R., Da Silva Antunes, R., Roman Aguilera, A.R, Tamada, K., and Croft, M. 2015. Tumor necrosis factor superfamily 14 (LIGHT) controls thymic stromal lymphopoietin to drive pulmonary fibrosis. Journal of Allergy and Clinical Immunology. 136:757.

Da Silva Antunes, R., Madge, L., Soroosh, P., Tocker, J., and Croft, M. 2015. The TNF family molecules LIGHT and lymphotoxin ab induce a distinct steroid-resistant inflammatory phenotype in human lung epithelial cells. Journal of Immunology. 195:2429.

Herro, R., Da Silva Antunes, R., Aguilera, A.R., Tamada, K., and Croft, M. 2015. The tumor necrosis factor superfamily molecule LIGHT promotes keratinocyte activity and skin fibrosis. Journal of Investigative Dermatology. 135:2109.