T
cells capable of responding to any given pathogen are very rare in a naive immune system (see panel 1 of figure below). This is actually a good thing, because it allows the immune system to fight a large number of possible infections - by using its resources to keep many TCRs, each specific for a different potential threat. During an infection , T cells specific for that particular pathogen (the red TCRs in panel 2 of figure below), divide rapidly by a process of "clonal expansion" . Once these T cells become effector T cells and clear or contain the pathogen, their job is done. However, instead of returning the number of these T cells to pre-infection frequencies, the system keeps 10-100 fold more of these cells around to build a faster response against any future re-infection (see panel 3 of figure below). This cohort, provides memory in the T cell compartment and is the mark left behind by every infection or vaccination that elicits lifelong protection in the host. If the host is to be ideally protected from all these infections, not only must these memory T cells find ways to survive in the body for extended periods of time (for a life time) but they should also do so without interfering with the survival of other memories (see panel 4 in the figure below). The projects in our lab examine the mechanisms evolved to ensure that a diverse repertoire is maintained in the immune system.
Project:
Maintenance of memory T cells has been extensively studied. The survival of these cells critically requires cytokines (IL-7, IL-15 etc) and at least for CD8 memory, involves a slow cell division that replenishes memory cells in the absence of their actual target antigen (agonist). We and others have found that for CD4 memory, the requirement for cytokine-driven basal proliferation is less stringent. Instead each antigen-specific CD4 T cell depends on unique low affinity self ligands for survival in vivo (see Singh et. al., Immunity 2012). We refer to these self-ligands as Sub-Threshold-Ligands (or STLs). We propose that the advantage of evolving STL-recognition in memory T cell survival is that it avoids rampant competition between unrelated memory T cells (see Figure below - click 2). This allows us to segregate the total memory T cell population in a host into "colonies" or distinct competitive units based on their ability to live off of different STLs. Since there are thousands of potential STLs, the immune system can hypothetically support thousands of such colonies - which allows for a mechanism to stably maintain a very diverse memory repertoire.
C
urrent projects in the lab evaluate this hypothesis in the context of infectious disease models (Plasmodium, Leishmania) and tumors using cellular and molecular approaches. These include experiments to measure the relative dependence of memory T cells on STLs vs Cytokines, the range of the repertoire that is maintained by a particular STL, the impact of inflammation and costimulation on STL-based competition etc. We are also interested in understanding how T cells sense STLs. An intriguing finding is that even strong agonists cannot replace STLs for the pro-survival signal that CD4 T cells require in vivo. How does the same TCR discriminate between an agonist and an STL ? A potential impact of these studies is in the development of an entirely new generation of adjuvants that improve specific-memory ...without a broad inflammatory response. Finally we are developing assays to identify STLs for T cells whose agonists are known. This is crucial in order to extend these studies to a broader spectrum of contexts.
