"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
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. Dr. Tony Fauci, NIH, referred to some of the Crotty lab work as “exceedingly important to the field of immunogen design.”
Dr. Crotty is a member of the LJI Coronavirus Taskforce. The Crotty Lab, in close collaboration with the lab of LJI Professor Alessandro Sette, Dr. Biol. Sci., was the first to publish a detailed analysis of the immune system’s response to SARS-CoV-2, the virus that causes COVID-19 (Cell, May 2020). The made a number of important findings. Most importantly, it showed that the immune system activates all three major branches of “adaptive immunity” (which learns to recognize specific viruses) to try to fight the virus: CD4 “helper” T cells , CD8 “killer” T cells, and antibodies. The LJI team found good immune responses to multiple different parts of SARS-CoV-2 (imagine the virus is made out of legos, and the immune system can recognize different individual legos), including the Spike protein, which is the main target of almost all COVID-19 vaccine efforts. This research helped dispel fears that the virus would elude efforts to create an effective vaccine. This scientific study had served as an important benchmark of immune responses for clinical studies and COVID-19 vaccine studies around the world, as evidenced by how extensively the study is being quoted (cited) in the scientific literature. It has also become the #1 most public attention getting Cell paper ever, according to Almetric.
Crotty and Sette also found that crossreactive immune memory appeared to exist in ~50% of unexposed, healthy people (Cell, May 2020). They inferred this might be due to previous infections with common cold coronaviruses. The LJI team went on to show that crossreactive memory T cells that recognize common cold coronaviruses also recognize matching sites on SARS-CoV-2 (Science, August 2020). The research may explain why some people have milder COVID-19 cases than others—though Crotty and Sette emphasize that this is speculation and much more data is needed (Nature Reviews Immunology, July 2020). Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Disease, has shared this research with Congress, describing the study as “work we really need to pursue. We’re just at the cusp of really understanding the importance of this type of response in COVID.”
The Crotty Lab’s COVID-19 research has informed vaccine efforts worldwide. As highlighted by Voice of America, this work builds on what scientists have learned about past vaccines and the experimental approaches that may bring a COVID-19 vaccine to patients quickly. As Dr. Crotty has said, “I think there is good reason for optimism, but it’s not like in the movies. It takes a lot of people and a lot of time and effort to puzzle it out.”
Cells important for vaccines
Most vaccines work because they generate antibodies. Dr. Crotty 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 helper T cells and, for many years, the wrong cell type was identified.” Dr. Crotty’s team showed that a new type of helper cell, “Tfh,” are required for antibody responses. His lab team set out to understand the inner workings of these critical cells in protective immune responses. “We discovered that the BCL6 gene was an on and off switch—a master regulator—in this process. In a series of experiments, we showed that if you turn on this gene, you get more helper cells, the Tfh type, and it is those cells that are telling the B cells to produce antibodies,” he said. The laboratory is now internationally recognized as the leader in Tfh cell biology, having elucidated critical aspects of Tfh cellular and molecular biology, which have been found to be not only important for vaccine biology but also in allergies, autoimmune diseases, and cancers.
New vaccine strategies
Dr. Crotty has a major focus studying human immune responses to vaccines. His lab is hard at work on candidate HIV vaccines with the CHAVID consortium. His lab is also hard at work on vaccine strategies for influenza, strep throat, and COVID-19. The Crotty lab studies new vaccine ideas and strategies that may be applicable to many diseases, based on a fundamental understanding of the underlying immune responses, and how the cells of the immune system interact. Last year the Crotty lab published that a simple slow delivery immunization strategy greatly improves the quality of vaccine responses (Cell 2019). The new strategy hinges on immune cell teamwork. Lead author Kimberly Cirelli, Ph.D., said, “It’s like physical training—you start off weak and then keep going back to the gym to get stronger. The germinal center is the gym and the B cells have to repeatedly go back to undergo rounds of selection to get better binding.” In 2020 the Crotty lab collaborated with Darrell Irvine’s lab at MIT to demonstrate a novel vaccine strategy (Nature Medicine 2020), with the labs hard at work on more new vaccine approaches.
Dr. Crotty regularly does media outreach on vaccines and immunity to infectious diseases. 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 and other publications. He earned his B.S. in Biology and Writing from Massachusetts Institute of Technology (MIT) in 1996, and his Ph.D. in Molecular Biology/Virology from the University of California, San Francisco (UCSF) in 2001.
From The Lab
Sep 16, 2020 // Cell
T cells take the lead in controlling SARS-CoV-2 and reducing COVID-19 disease severity
Finding may help explain why people 65 and above face a higher risk of falling critically ill with COVID-19
Do memory CD4 T cells keep their cell-type programming: plasticity versus fate commitment? Complexities of interpretation due to the heterogeneity of memory CD4 T cells including T follicular helper cells
Adjuvanting an simian immunodeficiency virus vaccine with toll-like receptor ligands encapsulated in nanoparticles induces persistent antibody responses and enhanced protection in TRIM5α restrictive macaques
Katsuri SP, Kozlowski PA, Nakaya HI, Burger MC, Russo P, Pham M, Kovalenkov Y, Silveira EL, Havenar-Daughton C, Burton…
Shane Crotty is a Professor with tenure of the La Jolla Institute for Immunology. 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.
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.
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.
I would like to pursue a career in vaccine research.
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.
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.
I want to pursue a career in T cell immunology in the context of gene regulation and T cell differentiation.
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.
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.
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.
I graduated from the University of Cincinnati with a B.A. in English Literature and a B.S. in Biology. From there, I attended graduate school at the University of Cincinnati and Cincinnati Children’s Hospital Medical Center investigating the role of natural killer cells in humoral immunity.
My project in the Crotty lab involves elucidating the characteristics of human follicular helper T cells, in human lymph nodes and the circulation, that contribute to protective humoral responses following immunization.
I’m interested in pursuing a career involved in improving human vaccine design and implementation to combat current and emerging global health threats.
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).