“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.
Shane Crotty is a Professor with tenure in the Vaccine Discovery Division. Dr. Crotty's research focus is on immune system memory, with particular interest in the roles of these mechanisms in human vaccines and protection from infectious diseases. By better understanding these processes, Dr. Crotty hopes new and better vaccines can one day be developed, particularly against deadly diseases like HIV, malaria, West Nile virus 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. This was important for the future development of new drugs that function like ribavirin but much better. 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 LIAI.
Dr. Crotty was named a Pew Scholar, marking him as one of the most promising young scientists in the country today. This distinction was given to only 14 other researchers in the country in 2005 and is coupled with a grant to aid Dr. Crotty in pursuing his research goals.
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, Journal of the American Medical Association (JAMA), Nature Medicine, Publishers Weekly, and Discover Magazine.
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 of the four varieties of CD4 helper type 2 cells (known as TH-2 cells) triggered the antibody process. But about 10 years ago, scientists realized this was incorrect and that there must exist a fifth 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.
Dr. Crotty's group also tested the finding by using a cellular mechanism to turn off the BCL6 gene. BLIMP1 is a potent antagonist of BCL6 expressed by some T cells. Turning off the gene stopped the production of the TFH cells. "Without this genetic trigger, no TFH cells were produced and consequently no antibodies." The researchers also found that the more TFH cells produced, the greater the antibody response.
Dr. Crotty also studies human immune responses to vaccines. immunological memory to the smallpox vaccine, which is considered the "gold standard" of vaccines because it led to the eradication of this disease. Interest in Dr. Crotty's research has been high because the younger portion of the U.S. population is not vaccinated against smallpox.
Another important way in which Dr. Crotty's lab studies immune memory is by understanding the function of a gene called SH2D1A or SAP. This gene is mutated in the human genetic disease XLP (X-linked lymphoproliferative disease). Children affected by this disease are immunodeficient and usually die from infectious diseases before reaching adulthood. Dr. Crotty has discovered that the SAP gene plays a central role in generation of immune memory. Understanding the role of SAP in greater detail may allow for the design of better human vaccines that take advantage of SAP's important role in the process of generating immune memory.
Unusual features of vaccinia virus extracellular virion form neutralization resistance revealed in human antibody responses to the smallpox vaccine. J Virol. 2013
Cutting edge: STAT1 is required for IL-6-mediated Bcl6 induction for early follicular helper cell differentiation. J Immunol. 2013
Dynamic regulation of Bcl6 in follicular helper CD4 (Tfh) cells. Curr Opin Immunol. 2013
Blc6 expressing follicular helper CD4 T cells are fate committed early and have the capacity to form memory. J Immunol. 2013
Modulation of SAP dependent T:B cell interactions as a strategy to improve vaccination. Curr Opin Virol. 2013
Human circulating PD-1+CXCR3-CXCR5+ memory Thf cells are highly functional and correlate with broadly neutralizing HIN antibody responses. Immunity. 2013
Harnessing CD4+ T cell responses in HIV vaccine development. Nat Med. 2013
The Receptor Ly108 Functions as a SAP Adaptor-Dependent On-Off Switch for T Cell Help to B Cells and NKT Cell Development
The 1-1-1 fallacy
Immunological Reviews. 2012
Bcl6 and Maf Cooperate To Instruct Human Follicular Helper CD4 T Cell Differentiation.
J Immunol. 2012
STAT5 is a potent negative regulator of TFH cell differentiation. J Exp Med. 2012
ICOS receptor instructs T follicular helper cell versus effector cell differentiation via induction of the transcriptional repressor Bcl6. Immunity. 2011
B cell-specific expression of B7-2 is required for follicular Th cell function in response to vaccinia virus. J Immunol. 2011
Follicular helper CD4 T cells (TFH) Annu Rev Immunol. 2011
IL-21 and IL-6 are critical for different aspects of B cell immunity and redundantly induce optimal follicular helper CD4 T cell (Tfh) differentiation. PLoS One. 2011
Protective murine and human monoclonal antibodies against eczema vaccinatum.
Antivir Ther. 2011
In vivo regulation of Bcl6 and T follicular helper cell development. J Immunol. 2010
Effectors and memories: Bcl-6 and Blimp-1 in T and B lymphocyte differentiation.
Nat Immunol. 2010
Germinal center T follicular helper cell IL-4 production is dependent on signaling lymphocytic activation molecule receptor (CD150). J Immunol. 2010
Combination therapy of vaccinia virus infection with human anti-H3 and anti-B5 monoclonal antibodies in a small animal model. Antivir Ther. 2010
The smallpox vaccine induces an early neutralizing IgM response. Vaccine. 2009
Heavily isotype-dependent protective activities of human antibodies against vaccinia virus extracellular virion antigen B5. J Virol. 2009
Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science 2009
Inhibition of NK cell activity by IL-17 allows vaccinia virus to induce severe skin lesions in a mouse model of eczema vaccinatum. J Exp Med 2009
Vaccinia virus extracellular enveloped virion neutralization in vitro and protection in vivo depend on complement.
J Virol. 2009
Quantitative PCR technique for detecting lymphocytic choriomeningitis virus in vivo.
J Virol Methods. 2008
OX40 drives protective vaccinia virus-specific CD8 T cells. J Immunol. 2008
Selective CD4+ T cell help for antibody responses to a large viral pathogen: deterministic linkage of specificities. Immunity. 2008
NKT cells prevent chronic joint inflammation after infection with Borrelia burgdorferi.
Proc Natl Acad Sci U S A. 2008
Redundancy and plasticity of neutralizing antibody responses are cornerstone attributes of the human immune response to the smallpox vaccine. Journal of Virology. 2008
SAP Regulation of Follicular Helper CD4 T Cell Development and Humoral Immunity Is Independent of SLAM and Fyn Kinase1. The Journal of Immunology. 2007
Vaccinia Virus H3L Envelope Protein Is a Major Target of Neutralizing Antibodies in Humans and Elicits Protection against Lethal Challenge in Mice. Journal of Virology. 2005
Profiling the humoral immune response to infection by using proteome microarrays: high-throughput vaccine and diagnostic antigen discovery. Proc Natl Acad Sci U S A. 2005
Tracking human antigen-specific memory B cells: a sensitive and generalized ELISPOT system.
J Immunol Methods. 2004
Immune responses to Bacillus anthracis protective antigen in patients with bioterrorism-related cutaneous or inhalation anthrax. J Infect Dis. 2004
Immunological memory in humans. Semin Immunol. 2004
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