Murray Research


Through a process of random genetic somatic recombination, each T lymphocyte in the mammalian body expresses a different antigen receptor that specifically binds to just one or a few antigens. This endows the immune system with the potential to respond to any pathogen it might encounter, but it also creates the dangerous possibility that some lymphocytes will bind to and damage the host’s own tissues, leading to autoimmunity. In addition, this process creates T cells specific for foreign histocompatibility antigens, and activation of these T cells causes transplant rejection and graft-versus-host disease. Thus, multiple layers of regulation are necessary to avoid inappropriate activation of lymphocytes, while maintaining the ability to respond robustly in the face of pathogen assault. I am interested in the molecular and cellular mechanisms that determine this delicate balance.

In Detail

I am studying the role of an intracellular signaling pathway called non-canonical NF-κB in T cell activation. This pathway is activated downstream of a number of TNF receptor family members, and is crucial for proper development of lymphoid organs and for survival of B cells after egress from the bone marrow. However, the role of this pathway in T cells is less clear. We have shown that despite retaining their ability to clonally expand in response to TCR stimulation, T cells deficient in non-canonical NF-κB do not acquire effector function and are rendered harmless in a mouse model of graft-versus host disease. In contrast, when this pathway is overactivated in T cells, CD4 and CD8 T cells become overactivated, secrete copious pro-inflammatory cytokines, and cause lethal multi-organ autoimmunity in mice. In addition, activation of this pathway impairs the function of a subset of T cells called Foxp3+ regulatory T cells (Tregs). This subset provides crucial negative regulation for conventional T cell activation, and congenital deficiency of Tregs causes lethal autoimmunity in mice and humans. My research projects aim to a) identify additional TNF receptor family members upstream of non-canonical NF-κB in conventional and regulatory T cell subsets (so far we know of one, OX40), b) dissect the transcriptional changes associated with activation of this pathway in T cells, and c) elucidate the mechanism(s) by which this pathway impairs regulatory T cell differentiation, function, and possibility phenotypic stability.