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.

My lab is focused on understanding the signals that occur early in the response to infection that promote the development and function of long-lived memory T cells.  To accomplish this, we employ two models of acute infection in mice: the gram-positive bacteriaListeria monocytogenes, and a natural viral pathogen of mice, lymphocytic choriomeningitis virus (LCMV).  By using these models, we hope to pinpoint some of the events that selectively promote memory T cell differentiation in only a small subset (~5-10%) of responding T cells.  Most recently, we have found a crucial role for a cytokine called interleukin-2 (IL-2) in the differentiation of protective memory CD8⁺ T cells.  IL-2 is rapidly induced following infection and is important for sustained expansion of activated T cells.  We have found a novel role for this cytokine by observing that memory CD8⁺ 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 for the development of functionally responsive memory T cells.  Future research in our lab will focus on the molecular nature, timing and source of the signal that IL-2 delivers to T cells that promotes their differentiation into memory cells.

A second major arm of research in my lab focuses on the signals required for the differentiation of CD4⁺ memory T cells.  Following LCMV infection, naïve CD4⁺ T cells specific for the LCMV glycoprotein can undergo up to 20,000-fold expansion.  As the pathogen is cleared, ~5-10% of the effector cells transition into memory cells.  In a different infectious system, in which the LCMV glycoprotein is recombinantly expressed in Listeria monocytogenes as a model antigen, antigen-specific CD4⁺ T cells also undergo massive expansion.  Remarkably, despite receiving activation signals sufficient for rapid expansion and the acquisition of effector function, the responding CD4⁺ T cells do not differentiate into memory cells and rapidly undergo apoptosis.  This observation has provided an ideal model system for analyzing the cellular and molecular requirements for CD4⁺ memory T cell differentiation.