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Matthew Williams

Assistant Professor of Pathology

B.A. Brigham Young University

Ph.D. Emory University

Research

References

matthew.williams@path.utah.edu

Matt Williams' PubMed Literature Search

Research

Following viral or bacterial infection, numerous components of the immune response play a role in recognizing, engaging and eradicating the offending pathogen.  T cells are particularly central to protection from a wide variety of infections.  Protective T cell responses are characterized by the following features, among others: i) the ability to recognize specific determinants of the infecting pathogen; ii) the ability to divide rapidly and expand to large numbers upon activation triggered by pathogen recognition; iii) migration to specific sites of infection; iv) the production of soluble growth and stimulatory factors, called cytokines, that are crucial for host defense and antibody production; and v) the ability to directly recognize and eliminate pathogen-infected cells.  A final hallmark of a protective T cell response is the long-lived (in many cases life-long) persistence of memory T cells that specifically recognize the pathogen.  Because memory T cells persist at high frequencies and recognize the pathogen much more quickly than naïve T cells, they are able to provide rapid protection upon encountering the same pathogen a second time.  While many successful vaccines of the past have relied on the development of antibody responses or their protective effect, future disease challenges will require the induction of cell-mediated protection provided by T cells.

Most T cells that are activated in response to an infectious challenge die once the pathogen is cleared.  However, a small proportion survives and populates the memory T cell pool.  My lab is focused on understanding the fate decisions that occur early in the response to infection that promote the development and function of these long-lived memory T cells.  To accomplish this, we employ models of acute viral or bacterial infection in mice in which we can track in vivo T cell responses and pinpoint the events that selectively promote memory T cell differentiation.  We have previously discovered a crucial role for the cytokine Interleukin-2 (IL-2) in the differentiation of protective memory T cells.  Memory T cells generated in the absence of IL-2 signals are unable to provide adequate protection to a secondary infection with the same pathogen.  These findings have led us to conclude that IL-2 provides a critical signal during T cell activation for the development of functionally responsive memory T cells.  Our current research focuses on the molecular nature of the memory differentiation signal that IL-2 delivers to T cells.

A second major arm of research in my lab is to determine the cell-intrinsic signals required for the differentiation of memory T cells.  Following activation, T cells begin to divide rapidly can undergo up to 50,000-fold expansion.  As the pathogen is cleared, ~5-10% of the effector cells transition into memory cells.  While much of the memory differentiation signal is cell-extrinsic and driven by growth factors and cytokines, we are testing the hypothesis that cell-intrinsic signals, mediated by the unique T cell receptor (TCR) expressed by each T cell, plays a central role in determiniung and shaping the memory T cell repertoire.  We are using deep sequencing and retroviral expression approaches to track the fate of individual T cells within the anti-pathogen response to determine the extent to which the strength of the TCR signal during activation influences long-term fate within the memory T cell pool.

References