The pervasive influence of the immune system on human health and disease underscores the importance of mechanistic understanding of immune regulation under pathophysiological conditions. Modern immunology is built on the foundation of clonal selection and pattern recognition theories that emphasize innate and adaptive immune recognition in controlling immune responses.
Despite the compelling power of these theories to explain immune responses to infection, they are inadequate in addressing how autoreactive lymphocytes are tolerized, the ability of naïve and memory lymphocytes to be maintained in the absence of cognate antigens, and the mechanisms by which immune responses are regulated in the context of non-classical scenarios of antigen exposure such as cancer.
We have postulated that regulatory mechanisms, established by co-opting evolutionarily ancient cell signaling modules, work in concert with innate and adaptive sensing mechanisms to ensure well-ordered immune activities. To this end, studies from my laboratory have led to the elucidation of critical roles for TGF-beta, Notch, Foxo and nutrient-sensing pathways in the control of T lymphocyte development, homeostasis, tolerance, and memory, as well as innate and adaptive immune responses to cancer. A major current focus in the lab is to study how these conserved metazoan cell signaling modules are rewired in the immune system using diverse immunological, genetic, biochemical, and genomic approaches, and to exploit these regulatory pathways for disease therapy including cancer immunotherapy.