Nevil Singh is a graduate of the Tata Institute of Fundamental Research (TIFR, Bombay, India) where his thesis work focused on vaccine-antigens against the malarial parasite, Plasmodium falciparum. He then joined Ron Schwartz’s group at the NIAID, NIH for a post-doctoral fellowship, examining T cell tolerance to self-proteins. Subsequently, as a Research Scientist at the NIAID, he studied the mechanisms controlling the responsiveness and frequency of helper T cells. He joined the faculty of UMDSOM in 2013.
The adaptive immune system has an evolutionary mandate to protect the integrity of the host – predominantly by fighting off infectious agents. Nevertheless the machinery it uses to protect the host also has the potential to injure the body and cause debilitating autoimmune diseases. Understanding the regulatory networks that have evolved to maintain optimal protective immunity with minimal damage to the host is the focus of the Nevil lab. We employ mouse model systems to examine how these networks regulate T cells during autoimmune (arthritis, lupus, dermatitis etc.) and protective immune (malaria, tumors etc.) responses. The range of problems we are interested in fall into two broad questions/categories:
How is a diverse repertoire of T cells maintained in the immune system?
The specific T cells needed to fight any particular pathogen are found in the immune system as rare members of a diverse repertoire that is generated randomly in the thymus. A greater diversity ensures representation for T cells that can recognize a wider range of pathogens, but also increases the risk of autoimmunity. Furthermore, considerations such as space and metabolic demands limit the number of T cells (and therefore the actual diversity) that can be present in the immunological ecosystem. We are interested in understanding how the immune system chooses an optimal diversity – and maintains it over a lifetime of exposures to multiple infections and injuries. We recently described a principle by which T cells organize themselves as virtual “colonies” in vivo, based on the shared recognition of weak endogenous ligands for their TCRs (Immunity, Oct 19 2012). This allows the immune system to regulate the frequencies of individual antigen-specific T cells at a very high resolution. We are now examining how such an organization helps maintain T cell memory after sequential immune responses to pathogens, malignancies etc.
How is the antigen-sensitivity of individual T cells regulated?
T cell receptors can sense as low as one molecule of their target antigen and activate the T cells to mount noxious responses. While this is quite advantageous in initiating an immune response at the first sign of a pathogen, such a hair-trigger can be dangerous if the target turns out to be a self-antigen. How does the immune system limit the potential for such autoimmunity? We find that one helpful mechanism in this regard is embodied in the T cell’s ability to “tune” its TCR (see, Dr.s Grossman and Paul, PNAS, 89(21): 10365-10369, for a theoretical discussion). In this process, a T cell that is in the presence of its target antigen for a long time is able to adjust its TCR sensitivity such that it does not continue to be activated by this antigen. While this mechanism can limit self-destructive responses, it can also be exploited by chronic infections and malignancies – to evade protective responses. We are now dissecting the molecular architecture of T cell tuning using genetic and biochemical approaches. In addition, several strategies that modulate the tuning process are being evaluated in the context of improving T cell responsiveness to infections and tumors.