Crotty Lab

Crotty Lab

"Infectious diseases kill more people worldwide than any other single cause. That’s one of the main reasons I focus on vaccines. They really have the potential for improving lives and saving lives." — Shane Crotty, Ph.D. // Professor
Division of Vaccine Discovery

Overview

Shane Crotty, Ph.D., and his team study immunity against infectious diseases. They investigate how the immune system remembers infections and vaccines. By remembering infections and vaccines, the body is protected from becoming infected in the future. Vaccines are one of the most cost-effective medical treatments in modern civilization and are responsible for saving millions of lives. Yet, good vaccines are very difficult to design, and very few new vaccines have been made in the past 10 years. A better understanding of immune memory will facilitate the ability to make new vaccines.

Most vaccines work because they generate antibodies. Dr. Crotty recently made a seminal finding in how this process occurs (Science 2009). Dr. Crotty said it has been well established that antibody production is a multi-step process that involves interactions between several cellular players, key among them CD4 “helper” T cells, which are disease-fighting white blood cells that tell other cells to produce antibodies in response to infections. “There were different flavors of these CD4 helper T cells and, for many years, we, in the scientific community, thought that one variety of CD4 helper cells (known as Th2 cells) triggered the antibody process. But about 10 years ago, scientists realized this was incorrect and that there must exist a new variety of CD4 helper T cell that initiated antibody production. It was named Tfh.”

Dr. Crotty’s team set out to understand the inner workings of the Tfh pathway. “We discovered that the BCL6 gene was like an on and off switch, or master regulator, in this process. In a series of experiments, we showed that if you turn on this gene, you get more CD4 T helper cells (the Tfh type) and it’s those cells that are telling the B cells to produce antibodies,” he said. The laboratory is now internationally recognized as a leader in Tfh cell biology, having identified the central role of BCL6 in Tfh cells, and elucidated critical aspects of Tfh cellular and molecular biology in animals and humans.

The field of Tfh cell biology has grown rapidly since the seminal publications in 2009, and work from many labs has shown that Tfh cells are important regulators of autoimmune diseases and allergies, in addition to their critical roles in immunity to viruses and bacteria.

Dr. Crotty has a major focus studying human immune responses to vaccines. His lab is hard at work on candidate HIV vaccines with the CHAVI-ID consortium.

From The Lab

Dec 6, 2016 // The San Diego Union Tribune

Scientists inching ever closer to HIV vaccine

Nov 28, 2016

Opening the immune system's "black box"

Nov 17, 2016

LJI scientist Shane Crotty makes Thomson Reuter’s list of “The World’s Most Influential Scientific Minds”

Jul 5, 2016 // STAT News

Boosting the immune system by giving T cells a push

Jun 7, 2016 // Emory News Center

NIH awards Emory $35.6 million grant for research aimed at HIV/AIDS vaccine and cure

Crotty Lab

Publications

Proc Natl Acad Sci USA

Sustained antigen availability during ferminal center initiation enhances antibody responses to vaccination

2016-10
Tam HH, Melo MB, Kang M, Pelet JM, Foley MH, Hu JK, Kumari S, Crampton J, Baldeon AD, Sanders RW, Moore JP, Crotty S,…
J Immunol

Response to comment on "A cytokine-independent approach to identify antigen-specific human germinal center T follicular helper cells and rare antigen-specific CD4+ T cells in blood

2016-10
Dan JM, Havenar-Daughton C, Silvestri G, Sette A, Crotty S
Nat Immunol

Dances with cytokines, featuring TFH cells, IL-24 and B cells

2016-09
J Immunol

A cytokine-independent approach to identify antigen-specific human germinal center T follicular helper cells and rare antigen-specific CD4+ T cells in blood

2016-08
Dan JM, Lindestam Arlehamn CS, Weiskopf D, de Silva Antunes R, Havenar-Daughton C, Reiss SM, Brigger M, Bothwell M,…
J Immunol

Cytokine-independent detection of antigen-specific germinal center T follicular helper cells in immunized nonhuman primates using a live cell activation-induced marker technique

2016-08
Nat Immunol

A TRAF-like motif of the inducible costimulator ICOS controls development of germinal center TFH cells via the kinase TBK1

2016-07
Pedros C, Zhang Y, Hu JK, Choi YS, Canonigo-Balancio AJ, Yates JR 3rd, Altman A, Crotty S, Kong KF
Nat Immunol

Id2 reinforces TH1 differentiation and inhibits E2A to repress TFH differentiation

2016-07
Cell Immunol

Th1 versus Th2 T cell polarization by whole-cell and acellular childhood pertussis vaccines persists upon re-immunication in adolescence and adulthood

2016-06
Bancroft T, Dillon MB, de Silva Antunes R, Paul S, Peters B, Crotty S, Lindestam Arlehamn CS, Sette A
PLoS One

CRISPR-mediated slamf1_/_ slamf5_/_ slamf6_/_ triple gene disruption reveals NKT cell defects but not T follicular helper cell defects

2016-05
Hu JK, Crampton JC, Locci M, Crotty S
Science

HIV-1 broadly neutralizing antibody precursor B cells revealed by germline-targeting immunogen

2016-03
Science

HIV-1 broadly neutralizing antibody precursor B cells revealed by germline-targeting immunogen

2016-03
J Virol

Linear epitopes in vaccinia virus A27 are targets of protective antibodies induced by vaccination against smallpox

2016-03
Kaever T, Matho MH, Meng Z, Crickard L, Schlossman A, Xiang Y, Crotty S, Peters B, Zajonc DM
Proc Natl Acad Sci USA

CXCL13 is a plasma biomarker of germinal center activity

2016-03
J Immunol

Cutting edge: NFAT transcription factors promote the generation of follicular helper T cells in response to acute viral infection

2016-03
Martinez GJ, Hu JK, Pereira RM, Crampton JS, Togher S, Bild N, Crotty S, Rao A
J Immunol

Cutting edge: NFAT transcription factors promote the generation of follicular helper T cells in response to acute viral infection

2016-03
Martinez GJ, Hu JK, Pereira RM, Crampton JS, Togher S, Bild N, Crotty S, Rao A
J Virol

Linear epitopes in A27 are targets of protective antibodies induced by vaccination against smallpox

2016-02
Kaever T, Matho MH, Meng Z, Crickard L, Schlossman A, Xiang Y, Crotty S, Peters B, Zajonc DM
Proc Natl Acad Sci USA

CXCL13 is a plasma biomarker of germinal center activity

2016-02
PLoS Pathog

Broadly neutralizing antibody responses in a large longitudinal sub-Saharan HIV primary infection cohort

2016-01
Landais E, Huang Z, Havenar-Daughton C, Murrell B, Price MA, Wickramasinghe L, Ramos A, Bian CB, Simek M, Allen S,…
PLoS Pathog

Broadly neutralizing antibody responses in a large longitudinal sub-Saharan HIV primary infection cohort

2016-01
Landais E, Huang Z, Havenar-Daughton C, Murrell B, Price MA, Wickramasinghe L, Ramos A, Bian CB, Simek M, Allen S,…
Journal of Immunology

Reversible reprogramming of circulating memory T follicular helper cell function during chronic HIV infection

2015-12
Cubas R, van Grevenynghe J, Wills S, Kardava L, Santich BH, Buckner CM, Muir R, Tardif V, Nichols C, Procopio F, He Z,…
Cell

Immunogenicity of stabilized HIV-1 envelope trimmers with reduced exposure of non-neutralizing epitopes

2015-12
de Taeye SW, Ozorowski G, Torrents de la Peña A, Guttman M, Julien JP, van den Kerkhof TL, Burger JA, Pritchard LK,…
Journal of Virology

Murine antibody responses to cleaved soluble HIV-1 envelope trimers are highly restricted in specificity

2015-10
Hu JK, Crampton JC, Cupo A, Ketas T, van Gils MJ, Sliepen K, de Taeye SW, Sok D, Ozorowski G, Deresa I, Stanfield R,…
Proceedings of the National Academy of Sciences of the United States of America

Bcl6 middle domain repressor function is required for T follicular helper cell differentiation and utilizes the corepressor MTA3

2015-10
Nance JP, Bélanger S, Johnston RJ, Hu JK, Takemori T, Crotty S
Nature Immunology

LEF-1 and TCF-1 orchestrate TFH differentiation by regulating differentiation circuits upstream of the transcriptional repressor Bcl6

2015-09
Choi YS, Gullicksrud JA, Xing S, Zeng Z, Shan Q, Li F, Love PE, Peng W, Xue HH, Crotty S
PLoS Pathogens

Structural and functional characterization of anti-A33 antibodies reveal a potent cross-species orthopoxviruses neutralizer

2015-09
Matho MH, Schlossman A, Meng X, Benhnia MR, Kaever T, Buller M, Doronin K, Parker S, Peters B, Crotty S, Xiang Y,…
Proceedings of the National Academy of Sciences of the United States of America

Dengue virus infection elicits highly polarized CX3CR1+ cytotoxic CD4+ T cells associated with portective immunity

2015-08
Weiskopf D, Bangs DJ, Sidney J, Kolla RV, De Silva AD, de Silva AM, Crotty S, Peters B, Sette A
Journal of Immunology

Cutting edge: T follicular helper cell differentiaion is defective in the absence of Bcl6 BTB repressor domain function

2015-06
Nance JP, Bélanger S, Johnston RJ, Takemori T, Crotty S
Trends in Immunology

In vivo RNAi screens: concepts and applications

2015-05
Crotty S, Pipkin ME
Journal of Experimental Medicine

BCL6 orchestrates Tfh cell differentiation via multiple distinct mechanisms

2015-04
Hatzi K, Nance JP, Kroenke MA, Bothwell M, Haddad EK, Melnick A, Crotty S
Nature Reviews Immunology

A brief history of T cell help to B cells

2015-03
Crotty S
Immunity

The transcription factor NFAT promotes exhaustion of activated CD8(+) T cells

2015-02
Martinez GJ, Pereira RM, Änjö T, Kim EY, Marangoni F, Pipkin ME, Togher S, Heissmeyer V, Zhang YC, Crotty S, Lamperti…
PLoS Pathogens

Murine anti-vaccinia virus D8 antibodies target different epitopes and differ in their ability to block D8 binding to CS-E

2014-12
Matho MH, de Val N, Miller GM, Brown J, Schlossman A, Meng X, Crotty S, Peters B, Xiang Y, Hsieh-Wilson LC, Ward AB,…
Immunity

T follicular helper cell differentiation, function, and roles in disease

2014-10
Crotty, S
Journal of Virology

Potent neutralization of vaccinia virus by divergent murine antibodies targeting a common site of vulnerability in L1 protien

2014-10
Kaever T, Meng X, Matho MH, Schlossman A, Li S, Sela-Culang I, Ofran Y, Buller M, Crump RW, Parker S, Fraizer A, Crotty…
Immunity

In vivo RNA interference screens identify regulators of antiviral CD4(+) and CD8(+) T cell differentiation

2014-08
Chen R, Bélanger S, Frederick MA, Li B, Johnston RJ, Xiao N, Liu YC, Sharma S, Peters B, Rao A, Crotty S, Pipkin ME
Journal of Immunology

Early lymphoid responses and germinal center formation correlate with lower viral load set points and better prognosis of simian immunodeficiency virus infection

2014-07
Hong JJ, Smacha PK, Rogers KA, Courtney CL, Havenar-Daughton C, Crotty S, Ansari AA, Villlinger F
Nature Immunology

The transcription factor FoxP1 is a critical negative regulator of the differentiation of foccicular helper T cells

2014-07
Wang H, Geng J, Wen X, Bi E, Kossenkov AV, Wolf AL, Tas J. Choi YS, Takata H, Day TJ, Cahng LY, Sprout SL, Becker EK,…
Nature Immunology

The E3 ubiquitin ligase Itch is required for the differentiation of follicular helper T cells

2014-07
Xiao N, Eto D, Elly C, Peng G, Crotty S, Liu YC
Structure

Using a combined computational-exterimental approach to predict antibody-specific B cell epitopes

2014-04
Sela-Culang I, Benhnia MR, Matho MH, Kaever T, Maybeno M, Scholossman A, Nimrod G, Li S, Ziang Y, Zajonc D, Crotty S,…
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
Immunity

Human circulating PD-1+CXCR3-CXCR5+ memory Tfh cells are highly functional and correlate with broadly neutralizing HIN antibody responses

2013-10
Locci M, Havenar_Daughton C, Landais E, Wu J, Kroenke MA, Arlehamn, CL, Su LF, Cubas R, Davis MM, Sette A, Haddad EK,…
Current Opinion in Immunology

Dynamic regulation of Bcl6 in follicular helper CD4 T (Tfh) cells

2013-06
Choi YS, Yang JA, Crotty S
Current Opinion in Virology

Modulation of SAP dependent T:B cell interactions as a strategy to improve vaccination

2013-06
Hu J, Havenar-Daughton C, Crotty S
Journal of Immunology

Blc6 expressing follicular helper CD4 T cells are fate committed early and have the capacity to form memory

2013-04
Choi YS, Yang JA, Yusuf I, Johnston RJ, Greenbaum J, Peters B, Crotty S
Nature Medicine

Inadequate T follicular cell help impairs B cell immunity during HIV infection

2013-04
Cubas RA, Mudd JC, Savoye AL, Perreau M, van Grevenynghe J, Metcalf T, Connick E, Meditz A, Freeman GJ, Abesada-Terk G…
Journal of Virology

Unusual features of vaccinia virus extracellular virion form neutralization resistance revealed in human antibody responses to the smallpox vaccine

2013-02
Behnnia MR, Maybeno M, Blum D, Agular-Sino R, Matho M, Meng X, Head S, Felgner PL, Zajonc DM, Koriazova L, Katho S,…
Nature Medicine

Harnessing CD4+ T cell responses in HIV vaccine development

2013-02
Streeck H, D'Souza MP, Littman DR, Crotty S
Cell Host & Microbe

A blueprint for HIV vaccine discovery

2012-10
Burton DR, Ahmed R, Barouch DH, Butera ST, Crotty S, Godzik A, Kaufmann DE, McElrath MJ, Nussenzweig MC, Pulendran B,…
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 Virology

Structural and biochemical characterization of the vaccinia virus envelope protein D8 and its recognition by the antibody LA5

2012-08
Matho MH, Maybeno M, Benhnia MR, Becker D, Meng X, Xiang Y, Crotty S, Peters B, Zajonc DM
Immunity

The receptor Ly108 functions as a SAP adaptor-dependent on-off switch for T cell help to B cells and NKT cell development

2012-06
Kageyama R, Cannons JL, Zhao F, Yusuf I, Lao C, Locci M, Schwartzberg PL, Crotty S
Immunological Reveiws

The 1-1-1 fallacy

2012-05
Crotty S
Journal of Immunology

Bcl6 and maf cooperate to instruct human follicular helper CD4 T cell differentiation

2012-04
Kroenke MA, Eto D, Locci M, Cho M, Davidson T, Haddad EK, Crotty S
Journal of Experimental Medicine

STAT5 is a potent negative regulator of TFH cell differentiation

2012-02
Johnston RJ, Choi YS, Diamond JA, Yang JA, Crotty S
Virology

An epitope conserved in orthopoxvirus A13 envelope protein is the target of neutralizing and protective antibodies

2011-09
Xu C, Meng X, Yan B, Crotty S, Deng J, Xiang Y
Immunity

ICSO receptor instructs T follicular helper cells versus effector cell differentiation via induction of the transcriptional reporessor Bcl6

2011-06
Choi YS, Kageyama R, Eto D, Escobar TC, Johnston RJ, Monticelli L, Lao C, Crotty S
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,…
Annual Review of Immunology

Follicular helper CD4 T cells (TFH)

2011-04
Crotty S
PLoS One

IL-21 and IL-6 are critical for differental aspects of B cell immunity and redundantly induce optimal follicular helper CD4 T cell (Tfh) differentiation

2011-03
Eto D, Lao C, Ditoro D, Barnett B, Escobar TC, Kageyama R, Yusuf I, Crotty S
Nat Immunol

Activin A programs the differentiation of human TFH cells

2009-07
Locci M, Wu JE, Arumemi F, Mikulski Z, Sahlberg C, Miller AT, Crotty S
Methods in Molecular Biology

Retroviral vector expression in TCR transgenic CD4(+) T cells

2005-07
Choi YS, Crotty S
Journal of Immunology

Cutting edge: STAT1 is required for IL-6-mediated Bcl6 induction for early follicular helper cell differentiation

0213-04
Choi YS, Eto D, Yang JA, Lao C, Crotty S
Cell Immunol

Th1 versus Th2 T cell polarization by whole-cell and acellular childhood pertussis vaccines persists upon re-immunication in adolescence and adulthood

2016-06
Bancroft T, Dillon MB, de Silva Antunes R, Paul S, Peters B, Crotty S, Lindestam Arlehamn CS, Sette A
Proc Natl Acad Sci USA

CXCL13 is a plasma biomarker of germinal center activity

2016-03
Havenar-Daughton C, Lindqvist M, Heit A, Wu JE, Reiss SM, Kendric K, B_langer S, Kasturi SP, Landais E, Akondy RS,…
PLoS One

Protection of rabbits and immunodeficient mice against lethal poxvirus infections by human monoclonal antibodies

2016-12
Crickard L, Babas T, Seth S, Silvera P, Koriazova L, Crotty S
Antiviral Therapy

Protective murine and human monoclonal antibodies against eczema vaccinatum

2016-12
Tomimori Y, Kawakami Y, McCausland MM, Ando T, Koriazova L, Kato S, Kawakami T, Crotty S
Proc Natl Acad Sci USA

CXCL13 is a plasma biomarker of germinal center activity

1969-12
J Immunol

A cytokine-independent approach to identify antigen-specific human germinal center T follicular helper cells and rare antigen-specific CD4+ T cells in blood

2016-06
Dan JM, Lindestam Arlehamn CS, Weiskopf D, da Silva Antunes R, Havenar-Daughton C, Reiss SM, Brigger M, Bothwell M,…
J Immunol

Cytokine-independent detection of antigen-specific germinal center T follicular helper cells in immunized nonhuman primates using a live cell activation-induced marker technique

2016-06
Havenar-Daughton C, Reiss SM, Carnathan DG, Wu JE, Kendric K, Torrents de la Pe_a A, Kasturi SP, Dan JM, Bothwell M,…
PLoS One

CRISPR-mediated slamf1_/_ slamf5_/_ slamf6_/_ triple gene disruption reveals NKT cell defects but not T follicular helper cell defects

2016-05
Hu JK, Crampton JC, Locci M, Crotty S
J Virol

Linear epitopes in vaccinia virus A27 are targets of protective antibodies induced by vaccination against smallpox

2016-04
Kaever T, Matho MH, Meng Z, Crickard L, Schlossman A, Xiang Y, Crotty S, Peters B, Zajonc DM
PLoS Pathog

Broadly neutralizing antibody responses in a large longitudinal sub-Saharan HIV primary infection cohort

2016-01
Landais E, Huang Z, Havenar-Daughton C, Murrell B, Price MA, Wickramasinghe L, Ramos A, Bian CB, Simek M, Allen S,…

Principal Investigator

crotty

Shane Crotty, Ph.D.

Professor

Shane Crotty is a Professor with tenure in the Vaccine Discovery Division. Dr. Crotty’s research focus is on the underlying immunology of vaccines, particularly the development of potent antibody responses and memory, with a predominant focus on the important role of CD4 T cells in these processes. By better understanding these processes, Dr. Crotty hopes new and better vaccines can one day be developed, particularly against deadly diseases like HIV, malaria, and tuberculosis, where no good vaccines currently exist.

Dr. Crotty received his B.S. in Biology from the Massachusetts Institute of Technology (MIT) in 1996. He also received a B.S. in Writing from MIT the same year. Dr. Crotty undertook graduate work in virology at the University of California, San Francisco in the Program in Biological Sciences. There he discovered the mechanism of action of the antiviral drug ribavirin, widely used to treat chronic hepatitis C infections. Dr. Crotty earned his Ph.D. in Biochemistry and Molecular Biology in 2001. He then pursued postdoctoral work at the Emory University Vaccine Center with Dr. Rafi Ahmed from 2001 to 2003, studying aspects of the generation and maintenance of immune memory after viral infections. In 2003, he accepted a faculty position at LJI.

The Crotty lab has helped established that follicular helper T cells (Tfh) are a distinct type of differentiated CD4 T cell uniquely specialized in B cell help, and that Tfh differentiation is controlled by the transcription factor Bcl6 (Science 2009). He has made major advances in the area of T cell help to B cells, and through this work has become an internationally recognized leader in the field of Tfh cell biology (Annual Review of Immunology 2011). Dr. Crotty was named a Pew Scholar in Biomedical Sciences in 2005, and was the recipient of the annualAmerican Association of Immunologists (AAI) Investigator Award for outstanding early-career research contributions to the field of Immunology in 2012.

Dr. Crotty is also the author of Ahead of the Curve, a biography of Nobel laureate scientist David Baltimore, published in 2001, and reviewed in The Wall Street Journal, Nature, The Washington Post, The Journal of the American Medical Association (JAMA), Nature Medicine, and Discover Magazine.

Lab Members

Robert Abbott

Postdoctoral Fellow

SimonBelanger

Simon Belanger

Postdoctoral Fellow

Biosketch:
I graduated from McGill University in Montréal, Canada in 2006 with a B.Sc. degree in Immunology. I then obtained my Ph.D. in Microbiology and Immunology from McGill University in 2012. I joined the Crotty lab as a postdoctoral fellow in February 2012.

Research Focus:
T follicular helper (Tfh) cells are required for the production of highly effective antibody responses and a better understanding of the development of Tfh will be critical in the development of more effective vaccines. I am interested in understanding the molecular pathways regulating the differentiation of Tfh cells after viral infection or vaccination using a novel in vivo screening approach we developed in the laboratory.

Career Goals:
I would like to pursue a career in vaccine research.

JinYong

Jinyong Choi

Postdoc

Biosketch:
I graduated with a B.S. degree in Biological Sciences in 2004 and obtained my Ph.D. in Biological Science in 2012 from Seoul National University in Seoul, South Korea. I then moved to Northwestern University School of Medicine and worked as a postdoctoral fellow. I joined the Crotty lab as a postdoctoral fellow in August 2015.

Research Focus:
Follicular helper T cells (Tfh cells) are specialized effector CD4+ T cells that help B cells develop germinal centers (GCs) and memory. Bcl6 is a lineage defining transcription factor of Tfh cells, but the functions of Bcl6 in Tfh cells have largely remained unclear. I am interested in the molecular mechanism of Bcl6 on the Tfh differentiation including its domains function, transcriptional regulation and epigenetic control.

Career Goals:
I want to pursue a career in T cell immunology in the context of gene regulation and T cell differentiation.

Kimberly Cirelli

Postdoc

Jordan Crampton

Research Technician

JenniferDan

Jennifer Dan

Postdoctoral Fellow

Biosketch:
I graduated from The University of Tennessee, Knoxville in 2002 with a B.S. in Biochemistry and Cellular and Molecular Biology and a B.A. in Classics (Latin). Afterward, I entered the MD/PhD program at Boston University School of Medicine. I obtained my Ph.D. in the Department of Microbiology, Immunology Training Program. I then matched into the Physician Scientist Training Program at the University of California, San Diego in 2010. I completed my Internal Medicine Residency in June 2012 (Internal Medicine Board 2013). I entered the Infectious Disease Fellowship in July 2012 (Infectious Disease Board 2015). I joined the Crotty laboratory in July 2013.

Research Focus:
My research focuses on understanding why some children get recurrent Group A Streptococcus tonsillitis or strep throat. T follicular helper (Tfh) cells are essential in making finely tuned antibodies to opsonize the bacteria. I am interested in discerning if there are strep-specific defects which may account for recurrent episodes of strep throat in children.

Career Goals:
I want to pursue translational research projects with a focus on immunosuppressed individuals, as they are more prone to infection. These individuals may be immunosuppressed due to chronic immune suppression for autoimmune diseases, hematopoietic or solid organ transplantation, age, or HIV infection.

Colin Havenar-Daughton

Postdoctoral Fellow

Kirti Kaushik

Research Technician

Jeong Hyun (JH) Lee

Postdoctoral Fellow

Michela_Locci

Michela Locci

Instructor

Biosketch:
I graduated cum laude from University of Bologna (Italy) in 2005 with a Master degree in Industrial Biotechnology. I then obtained my Ph.D. in Immunology and Applied Biotechnology from Tor Vergata University (Rome, Italy) in 2010. I joined the Crotty lab as a postdoctoral fellow in July 2011, and I was promoted to instructor in May 2016.

Research Focus:

T follicular helper (Tfh) cells are a subset of CD4 T cells highly specialized in aiding B cell responses. Hence, manipulating the frequency and the quality of Tfh responses has significant potential for all clinical applications in which the modulation of Ab responses is desired. Human memory Tfh cell functional heterogeneity and Tfh cell differentiation are the focus of my research. As a postdoctoral fellow, I conducted a study in which I identified a population of memory Tfh cells in human blood that phenotypically and functionally resembled bona fide Tfh cells, and that can be used as biomarker to predict the ability of HIV+ individuals to develop broadly neutralizing Abs against HIV (Locci et. al. Immunity 2013). A second large study that I carried out focused on the identification of novel regulators of human Tfh cell differentiation. I performed a high-throughput screen of human recombinant molecules and identified the cytokine activin A as important player in the regulation of human Tfh cell differentiation and function (Locci et al. Nature Immunology, in press).

Career Goals:

My long-term goal is to become an independent investigator and establish a research program aimed to elucidate crucial aspects of B cell regulation by T follicular helper (Tfh) cells in human health and disease.

Samantha_Reiss

Samantha Reiss

Research Technician

Biosketch:
I graduated from UC San Diego with a Bachelor of Science and then a Master of Engineering in Bioengineering and Biotechnology, with a focus in Tissue Engineering and Regenerative Medicine. During this time I also studied biomaterials and nanotechnology. During school I worked at a regenerative medicine company called Histogen, and upon graduation I joined Peter Kuhn’s laboratory at the Scripps Research Institute studying circulating tumor cells in the blood.

Research Focus:
In 2014 I joined Dr. Shane Crotty’s laboratory studying Germinal Center T Follicular Helper Cells (GC Tfh), in particular with regards to informing the efforts towards developing immunogens for a broadly neutralizing HIV vaccine. Most recently my work has focused on the development and application of an assay to detect antigen-specific T cells in rhesus macaques.

Career Goals:
I’m passionate about bringing scientific discoveries to real world patients.

MeganRossi

Meghan Rossi

Research Technician

Biosketch:
I graduated from Berkeley in May of 2012 with a degree in Molecular and Cell Biology, and recently received a Master’s degree with first-class honors in Neurosciences from University College London examining neuronal mechanisms of spatial navigation. While undertaking my undergraduate degree, I also studied double-strand DNA break repair mechanisms at Lawrence Berkeley National Lab, as well as adverse neurological effects of anesthetic compounds at UC San Francisco. Between my degrees, I spent time at Oxford University investigating antibody-mediated diseases of the central nervous system in the department of Neuroimmunology.

Research Focus:
In the spring of 2016 I joined Dr. Shane Crotty’s laboratory to investigate the inability of mice to generate tier 2 broadly neutralizing HIV antibodies, with the overall aim of developing an HIV vaccine able to elicit broadly neutralizing antibodies in humans.

Career Goals:
Continue to build upon my technical skills and scientific knowledge to investigate human systems and disease, with the goal of improving health and quality of life.

Laura Toy

Research Technician

Crotty Lab

Research Projects

Our overall goal is to understand the process of CD4 T cell control of the generation of long-term humoral immunity as it relates to new vaccine development. Long term humoral immunity, and as such are critically important for protection against many infectious diseases and are key components of the protection afforded by most vaccines. Long term humoral immunity predominantly depends on germinal centers. Follicular helper T cells (Tfh) are the specialized CD4 T cells for B cell help and are necessary for germinal centers. Tfh cells support B cell differentiation into affinity matured long-lived plasma cells and memory B cells by co-localizing with B cells and delivering costimulatory molecules and lymphokines that constitute the functional signature of this specific CD4 T cell subset. Furthermore, Tfh cells are needed for the crucial affinity maturation process of B cells in germinal centers, whereby antigen-specific B cells undergo repeated rounds of somatic hypermutation and positive selection by Tfh cells to rapidly evolve high affinity somatically mutated B cell receptors (BCR), resulting in the development of memory B cells and plasma cells with greater protective efficacy. In addition to being necessary for GCs, Tfh cells are also frequently limiting for the magnitude of the GC B cell and antibody responses. Therefore, there is widespread interest in manipulating Tfh cells to enhance vaccines

Designing vaccines: Differentiation and function of follicular helper CD4 T cells (Tfh cells)

A link to a video lecture on Tfh cell biology is here.

Germinal centers are the critical sites for the development of long term humoral immunity in the form of antigen-specific memory B lymphocytes and long-lived plasma cells. CD4 T cells are essential for germinal center function. Therefore it is vital to understand the role of CD4 T cell help to B lymphocytes to understand how to better generate long term humoral immunity to pathogens such as viruses and bacteria. (Reviews: Annual Review of Immunology, 2011; Immunity 2014; Nature Reviews Immunology 2015)

The Crotty lab has helped establish that follicular helper CD4 T cells (Tfh) are the uniquely specialized type of CD4 T cell required for germinal centers and most T-dependent humoral immune responses. We
and others established that Bcl6 is a critical transcription factor required for Tfh cell differentiation and function (Science 2009). SAP (Nature 2003, J. Immunology 2010), ICOS (Immunity 2011), B cells (Science 2009, Immunity 2011), IL-6 (PLoS One, 2011; JI Cutting Edge, 2014),
IL-21 (PLoS One 2011), and Itch (Nature Immunology 2014) all have important roles in Tfh cell differentiation. We have shown potent negative regulatory roles for IL-2 (JEM 2012), IL2Ra (CD25) (Immunity 2011, JEM 2012), STAT5 (JEM 2012), Blimp-1 (Science 2009, Immunity 2011, JEM 2012), and the pTEFb complex (Immunity 2014) in Tfh cell differentiation in vivo.

Tfh cells are conserved in humans and are key players in development of humoral immunity (Annual Review of Immunology, 2011; Immunity 2014). Tfh cells can also be major players in autoimmune diseases. Bcl6 is a critical transcription factor regulating Tfh cell differentiation in humans (J. Immunology 2012). Maf is a second transcription factor with important roles in Tfh cell differentiation (J. Immunology 2012). Highly functional memory Tfh cells are associated with potent neutralizing antibody responses in HIV+ individuals (Immunity 2013).

We are focused on understanding Tfh cell differentiation in sufficient detail to be able to manipulate Tfh cell differentiation to maximize Tfh cell responses in new vaccines to maximize the development of protective antibodies and the development of long term humoral immunity.

HIV Vaccine Research (AIDS Vaccine Research).

Broadly neutralizing antibodies have been discovered in ~5% of HIV+ individuals. Some of those antibodies (HIV bnAbs) are capable of neutralizing over 70% of all known HIV isolates. Finally, providing a single intravenous injection of a single HIV bnAb into macaques completely protects the animals from a lethal mucosal (vaginal) SHIV challenge. These three facts provide proof-of-principle that a neutralizing antibody HIV vaccine strategy could be highly protective in humans. However, while those proof-of-principle experiments have shown the validity of the concept, major scientific and
technical obstacles make most observers skeptical that a neutralizing antibody HIV vaccine will be possible. The Crotty laboratory, as part of the CHAVI-ID consortium, is intensively pursuing the idea that a neutralizing antibody HIV vaccine is possible (Burton et al., Cell Host and Microbe 2012), and it will depend on optimized Tfh cell and germinal center responses to driven the necessary affinity maturation to obtain HIV broadly neutralizing antibodies via immunization (Locci et al., Immunity 2013; Crotty Immunity 2014).