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. // Director, Scientific Affairs
Professor, Director of Scientific Affairs

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, but that also may contribute to inflammatory and autoimmune diseases. The TNFR molecules studied by Dr. Croft and his laboratory are expressed on T lymphocytes. other cells of the immune system, and tissue cells such as epithelial cells and fibroblasts, and emerging evidence is suggesting they crucially regulate the 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, and of OX40 in atopic dermatitis.

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 multiple 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 a permanent member or ad-hoc. He has served as Associate Editor and Section Editor of the Journal of Immunology and Frontiers in Immunology, and was a member of Faculty 1000 prime.

From The Lab

Jan 16, 2018 // Journal of Experimental Medicine

LJI researchers discover key driver of atopic dermatitis

May 22, 2017

TWEAKing inflammation

Croft Lab

Publications

Cell Rep

TLR9 Sensing of Self-DNA Controls Cell-Mediated Immunity to Listeria Infection via Rapid Conversion of Conventional CD4(+) T Cells to Treg

2020-04
Dolina JS, Lee J, Griswold RQ, Labarta-Bajo L, Kannan S, Greenbaum JA, Bahia El Idrissi N, Pont MJ, Croft M,…
J Immunol

4-1BBL Regulates the Polarization of Macrophages, and Inhibition of 4-1BBL Signaling Alleviates Imiquimod-Induced Psoriasis

2020-04
Miki H, Han KH, Scott D, Croft M and Kang YJ
FASEB J

IQGAP1 restrains T-cell cosignaling mediated by OX40

2020-01
Okuyama Y, Nagashima H, Ushio-Fukai M, Croft M, Ishii N and So T
Sci Rep

The protein tyrosine kinase syk regulates the alternative p38 activation in liver during acute liver inflammation

2019-11
Bang BR, Han KH, Seo GY, Croft M, Kang YJ
Sci Transl Med

Antibody-mediated targeting of tnfr2 activates cd8(+) t cells in mice and promotes antitumor immunity

2019-10
Tam EM, Fulton RB, Sampson JF, Muda M, Camblin A, Richards J, Koshkaryev A, Tang J, Kurella V, Jiao Y, Xu L, Zhang K,…
J Allergy Clin Immunol

Unconventional st2- and cd127-negative lung ilc2 populations are induced by the fungal allergen alternaria alternata

2019-07
Cavagnero KJ, Badrani JH, Naji LH, Amadeo MB, Shah VS, Gasparian S, Pham A, Wang AW, Seumois G, Croft M, Broide DH,…
J Biol Chem

Crystal structure of the m4-1BB/4-1BBL complex reveals an unusual dimeric ligand that undergoes structural changes upon 4-1BB receptor binding

2019-02
Bitra A, Doukov T, Destito G, Croft M, Zajonc DM
Am J Transplant

The TWEAK/Fn14 pathway is required for calcineurin inhibitor toxicity of the kidneys

2018-07
Claus M, Herro R, Wolf D, Buscher K, Rudloff S, Huynh-Do U, Burkly L, Croft M, Sidler D
Allergy

Tumor necrosis factor family member LIGHT acts with IL-1β and TGF-β to promote airway remodeling during rhinovirus infection

2018-07
Mehta AK, Doherty T, Broide D, Croft M
J Biol Chem

Crystal structures of the human 4-1BB receptor bound to its ligand 4-1BBL reveal covalent receptor dimerization as a potential signaling amplifier

2018-06
Bitra A, Doukov T, Croft M, and Zajonc DM
J Immunol

The TNF superfamily molecule LIGHT promotes the generation of circulating and lung-resident memory CD8 T cells following an acute respiratory virus infection

2018-04
Desai P, Tahiliani V, Hutchinson TE, Dastmalchi F, Stanfield J, Abboud G, Thomas PG, Ware CF, Song J, Croft M,…
Sci Transl Med

An OX40/OX40L interaction directs successful immunity to hepatitis B virus

2018-03
Publicover J, Gaggar A, Jespersen JM, Halac U, Johnson AJ, Goodsell A, Avanesyan L, Nishimura SL, Holdorf M, Mansfield…
Front Immunol

TNFSF14 (LIGHT) exhibits inflammatory activities in lung fibroblasts complementary to IL-13 and TGF-β

2018-03
da Silva Antunes R, Mehta AK, Madge L, Tocker J, Croft M
J Exp Med

LIGHT-HVEM signaling in keratinocytes controls development of dermatitis

2018-02
Herro R, Shui JW, Zahner S, Sidler D, Kawakami Y, Kawakami T, Tamada K, Kronenberg M, Croft M
J Biol Chem

Crystal structure of murine 4-1BB and its interaction with 4-1BBL support a role for galectin-9 in 4-1BB signaling

2018-01
Bitra A, Doukov T, Wang J, Picarda G, Benedict CA, Croft M, Zajonc DM
Cytokine

TNF activity and T cells

2018-01
Mehta AK, Gracias DT, Croft M
J Immunol

Rhinovirus infection of ORMDL3 transgenic mice is associated with reduced rhinovirus viral load and airway inflammation

2017-10
Song DJ, Miller M, Beppu A, Rosenthal P, Das S, Karta M, Vuong C, Mehta AK, Croft M, Broide DH
J Immunol

Regulatory T cell-mediated suppression of inflammation induced by DR3 signaling is dependent on galectin-9

2017-09
Madireddi S, Eun SY, Mehta AK, Birta A, Zajonc DM, Niki T, Hirashima M, Podack ER, Schreiber TH, Croft M
J Immunol

HVEM imprints memory potential on effector CD8 T cells required for protective mucosal immunity

2017-09
Desai P, Abboud G, Stanfield J, Thomas PG, Song J, Ware CF, Croft M, Salek-Ardakani S
J Immunol

Leukotriene C4 potentiates IL-33-induced group 2 innate lymphoid cell activation and lung inflammation

2017-08
Lund SJ, Portillo A, Cavagnero K, Baum RE, Naji LH, Badrani JH, Mehta A, Croft M, Broide DH, Doherty TA
Nat Commun

TWEAK mediates inflammation in experimental atopic dermatitis and psoriasis

2017-05
Sidler D, Wu P, Herro R, Claus M, Wolf D, Kawakami Y, Kawakami T, Burkly L, Croft M
Nat Rev Rheumatol

Beyond TNF: TNF superfamily cytokines as targets for the treatment of rheumatic diseases

2017-04
Croft M, Siegel RM
J Allergy Clin Immunol

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

2016-08
Miller M, Esnault S, Kurten RC, Kelly EA, Beppu A, Das S, Rosenthal P, Ramsdell J, Croft M, Zuraw B, Jarjour N, Hamid…
Front Immunol

How mouse macrophages sense what is going on

2016-06
Ley K, Pramod AB, Croft M, Ravichandran KS, Ting JP
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
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
European Journal of Immunology

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

2015-03
Bang BR, Kim SJ, Yagita H, Croft M, Kang YJ
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
Frontiers in Immunology

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

2012-11
Zhao Y, Tahiliani V, Salek-Ardakani S, Croft M
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
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

2012-05
So T, Croft M
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
Diabetes

Virtual optimization of nasal insulin therapy predicts immunization frequency to be crucial for diabetes protection

2010-12
Fousteri G, Chan JR, Zheng Y, Whiting C, Dave A, Bresson D, Croft M, von Herrath M
BMC Immunol

The antigen presentation function of bone marrow-derived mast cells is spatiotemporally restricted to a subset expressing high levels of cell surface FcepsilonRI and MHC II

2010-06
Gong J, Yang NS, Croft M, Weng IC, Sun L, Liu FT, Chen SS
Annu Rev Immunol

Control of immunity by the TNFR-related molecule OX40 (CD134)

2010-04
Croft M
J Allergy Clin Immunol

Innate signals from Nod2 block respiratory tolerance and program T(H)2-driven allergic inflammation

2010-12
Duan W, Mehta AK, Magalhaes JG, Ziegler SF, Dong C, Philpott DJ, Croft M
Am J Pathol

CD137 is required for M cell functional maturation but not lineage commitment

2010-08
Hsieh EH, Fernandez X, Wang J, Hamer M, Calvillo S, Croft M, Kwon BS, Lo DD
Eur J Immunol

Biphasic role of 4-1BB in the regulation of mouse cytomegalovirus-specific CD8(+) T cells

2010-10
Humphreys IR, Lee SW, Jones M, Loewendorf A, Gostick E, Price DA, Benedict CA, Ware CF, Croft M
J Interferon Cytokine Res

Tumor necrosis factor receptor/tumor necrosis factor family members in antiviral CD8 T-cell immunity

2010-04
Salek-Ardakani S, Croft M

Principal Investigator

Michael Croft, Ph.D.

Director, Scientific Affairs

Dr. Croft is a Professor at LJI and currently serves as Director of Scientific Affairs. 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, and became a Professor in 2005.

Lab Members

Rinkesh Gupta

Postdoc Fellow

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 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

Mario Cabero Manresa

Visiting Scientist

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 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.

Haruka Miki, Ph.D.

Postdoctoral Fellow

Jacqueline Miller, B.Sc

Research Tech 3

Biosketch:
I graduated from the University of California San Diego in 2010 with a B.S. degree in Bioengineering: Pre-medical. I began working as a Research Associate in the Von Herrath laboratory at the La Jolla Institute for Immunology in March 2011 and was promoted to the Research Associate II. In August 2013, I accepted my current position in the Ley laboratory as lab and mouse colony manager.

Research Focus:
The research projects I assist with focus on the roles of myeloid and T cells in atherosclerosis. I am interested in understanding the mechanisms and cellular players responsible for plaque formation and how immune tolerance can be medicated through vaccination in the future treatment of heart disease.

Career Goals:
I plan to pursue a career in clinical scientific research after obtaining a medical degree.

Gurupreet Sethi

Postdoctoral Fellow

Croft Lab

Research Projects

RESEARCH FOCUS

The focus of the Croft laboratory are costimulatory receptor-ligands that positively affect how well different cell types respond during inflammation, extending from autoimmunity to infectious disease to cancer. Specifically, the lab focuses on proteins of the TNF (tumor necrosis factor) and TNFR (tumor necrosis factor receptor) superfamily which are displayed as membrane molecules on the surface of many lymphoid as well as non-lymphoid cells and can also act as soluble cytokines. 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 various cells; and to determine the significance of these proteins in diseases such as asthma and atopic dermatitis. Because our current understanding suggests that these molecules control many functional activities, and their effects might extend to a number of cell types, they are therefore potential targets for either suppressing an immune response, or for promoting an immune response.

The TNF family molecules that have been studied in the lab over the years are named OX40L, 4-1BBL, LIGHT, TL1A, CD70, and TWEAK. Data from the laboratory shows that signals from these molecules through their receptors control the inflammatory activities and long-term survival of T cells as well as functional responses in non-lymphoid structural 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 has investigated whether agonist reagents that can signal various immune cells through the TNF family receptors can be used to increase natural immune responses to viruses or tumors that might lead to strategies for vaccination.

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. 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 diseases such as multiple sclerosis, rheumatoid arthritis, scleroderma, psoriasis, and diabetes, and inflammation such as characterized by allergies, asthma, and atopic dermatitis (eczema).

Our lab has worked on understanding how costimulatory receptors in the TNFR family control the activities of T cells in multiple scenarios. Much of this data and other relevant information can be found in the reviews listed below:

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.

Croft, M. 2014. The TNF family in T cell differentiation and function – Unanswered questions and future directions. Seminars in Immunology. 26:183.

Croft, M., and Siegel, R.M. 2017. Beyond TNF: TNF family cytokines as targets for the treatment of rheumatic diseases. Nature Reviews Rheumatology. 13:217.

Mehta, A.K., Gracias, D.T., and Croft, M. 2018. TNF activity and T cells. Cytokine. 101:14.


Specific examples of control of T cells by TNFR family proteins relate to the molecules OX40 (CD134), 4-1BB (CD137), CD27, HVEM, and CD30. For example, studies of knockout animals made deficient in these molecules or blocking studies with antibody 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 them. Several studies have also suggested that OX40 and 4-1BB signals can directly prevent suppressive activity or the induction of regulatory T cells which further aids the clonal expansion and differentiation of effector T cells. Studies in experimental animal models have now not only stressed the importance of the molecules for autoimmune and inflammatory disease manifestations, but shown that inhibiting these interactions can be useful therapeutically. For example, inhibiting OX40/OX40L interactions can abrogate Th2 or Th1/Th17-induced pathologies in experimental leishmaniasis, multiple sclerosis, graft-versus-host disease, transplantation, inflammatory bowel disease, asthma, atopic dermatitis and arthritis. Agonist reagents that stimulate OX40, 4-1BB, and CD27 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 and CD30 drives responses to allergens that link to asthmatic and allergic disease, and how these molecules control allergen-reactive effector and tissue-resident memory 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.

Bansal-Pakala, P., and Croft, M. 2002. Defective T cell priming associated with aging can be rescued by signaling through 4-1BB (CD137). Journal of Immunology. 169:5005.

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., Salek-Ardakani, S., Rogers, P.R., Cheng, M., Van Parijs, L., and Croft, M. 2004. The costimulation-regulated duration of PKB activation controls T cell longevity. Nature Immunology. 5:150

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.

Song, A., Tang, X., Harms, K.M., and Croft, M. 2005. OX40 and Bcl-xL promote the persistence of CD8 T Cells to recall tumor-associated antigen. Journal of Immunology. 175:3534.

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.

Song, A., Song, J., Tang, X., and Croft, M. 2007. Co-operation between CD4 T cells and CD8 T cells for anti-tumor activity is enhanced by OX40 signals. European Journal of Immunology. 37:1224.

Song, J., Salek-Ardakani, S., So, T., and Croft, M. 2007. The kinases aurora B and mTOR regulate the G1-S cell cycle progression of T lymphocytes. Nature Immunology. 8:64.

Salek-Ardakani, S., Moutaftsi, M., Crotty, S., Sette, and Croft, M. 2008. OX40 drives protective vaccinia virus-specific CD8 T cells. Journal of Immunology. 181:7969.

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.

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.

Salek-Ardakani, S., Moutafsi, M., Sette, A., and Croft, M. 2011. Targeting OX40 promotes lung resident memory CD8 T cell populations that protect against respiratory poxvirus infection. Journal of. Virology. 85:9051.

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.

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.

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.

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.

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.

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. 137:278

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
Tahiliani, V., Hutchinson, T.E., Abboud, G., Croft, M., and Salek-Ardakani, S. 2017. OX40 co-operates with ICOS to amplify follicular Th cell development and germinal center reactions during infection. Journal of Immunology. 198:218.

Madireddi, S., Eun, S-Y., Mehta, A.K., Birta, A., Zajonc, D.M., Niki, T., Hirashima, M., Podack, E., Schreiber, T., and Croft, M. 2017. Regulatory T cell-mediated suppression of inflammation induced by DR3 signaling is dependent on galectin-9. Journal of Immunology. 199:2721.

Desai, P., Abboud, G., Stanfield, J., Thomas, P.G., Song, J., Ware, C.F., Croft, M., and Salek-Ardakani, S. 2017. HVEM imprints memory potential on effector CD8 T cells required for protective mucosal immunity. Journal of Immunology. 199:2968.

Desai, P., Tahiliani, V., Hutchinson, T.E., Dastmalchi, F., Stanfield, J., Abboud, G., Thomas, P.G., Ware, C.F., Song, J., Croft, M., and Salek-Ardakani, S. 2018. The TNF superfamily molecule LIGHT promotes the generation of circulating and lung-resident memory CD8 T cells following an acute respiratory virus infection. Journal of Immunology. 200:2894.

STRUCTURAL CELLS

Non-lymphoid structural cells of tissues are recipients of inflammatory signals from immune cells, but they also make inflammatory products that can affect the migration, localization, and activity of immune cells in the tissues. Together this contributes to the pathologic changes that are seen in many diseases. In particular, epithelial cells, fibroblasts, and smooth muscle cells can become deregulated and contribute to fibrosis and tissue remodeling that impair normal organ functioning. This is often seen in chronic forms of autoimmunity or severe inflammatory diseases such as asthma or atopic dermatitis with overexuberant responses to allergens. TNF, that is the target of many FDA approved drugs for diseases such as psoriasis and rheumatoid arthritis, contributes to these processes as its primary receptor TNFR1 is expressed on most non-lymphoid structural cells. Similarly, a number of other TNF family receptors have now been found expressed on structural cells and their signals can bring about changes that are characteristic of disease. This includes driving the production of extracellular matrix proteins such as collagen, fibronectin, and fibrillin, that are products of fibroblasts and epithelial cells, and can restrict cellular spaces within tissues. It also includes making inflammatory cytokines such as TSLP and IL-33, or various chemokines, that act on many immune cell types, such as eosinophils, neutrophils, and macrophages, to promote their movement into tissues and drive their functional responses. Further activities include causing the differentiation of fibroblasts into smooth muscle-like cells, and also inducing an increase in the mass of smooth muscle cells and their contractility. The lab is currently focusing on how LIGHT, TL1A, and TWEAK promote responses in structural cells linked to diseases of the lung and skin, including asthma, idiopathic pulmonary fibrosis, systemic sclerosis, atopic dermatitis and psoriasis. Understanding how these TNF family proteins act, and how their combined signals drive tissue pathology, is likely to lead to new therapeutic approaches for limiting and resolving these types of disease.

Selected References

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.

Doherty, T.A., Khorram, N., Kotaro, Sheppard, D, Rosenthal, P., Cho, J.Y., Pham, A., Miller, M., Croft, M., and Broide, D. 2012. Alternaria induces STAT-6 dependent acute airway eosinophilia and epithelial FIZZ1 expression that promotes airway fibrosis and epithelial thickness. Journal of Immunology. 188:2622.

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.

Herro, R., and Croft, M. 2016. The control of tissue fibrosis by the inflammatory molecule LIGHT (TNF superfamily member 14). Pharmacology Research. 104:151.

Sidler, D., Wu, P., Herro, R., Claus, M., Kawakami, Y., Kawakami, T., Burkly, L, and Croft, M. 2017. TWEAK mediates inflammation in experimental atopic dermatitis and psoriasis. Nature Communications. 8:15395.

Herro, R., Shui, J., Zahner, S., Sidler, D., Kawakami, Y., Kawakami, T., Tamada, K., Kronenberg, M., and Croft, M. 2018. LIGHT-HVEM signaling in keratinocytes controls development of dermatitis. Journal of Experimental Medicine. 215:415.

Mehta, A.K., Doherty, T.A., Broide, D., and Croft, M. 2018. Tumor necrosis factor family member LIGHT acts with IL-1 and TGF- to promote airway remodeling during rhinovirus infection. Allergy. 73:1415.

Da Silva Antunes, R., Mehta, A.K., Madge, L., Tocker, J., and Croft, M. 2018. TNFSF14 (LIGHT) exhibits inflammatory activities in lung fibroblasts complementary to IL-13 and TGF-. Frontiers in Immunology. 9:576.