Pathology Presents: Everybody Needs a “Brake”: Role of Immunological Brakes in T cell Immunity
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Surojit Sarkar, PhD
Assistant Professor, Department of Pediatrics
University of Washington School of Medicine
Principal Investigator, BTCCCR, Seattle Children's Research Institute
- Faculty Sponsor
Bill Mahoney, PhD
Everybody Needs a “Brake”: Role of Immunological Brakes in T cell Immunity
Our immune system has a lot of similarities to a speeding automobile with a gas and a brake pedal. Just like a speeding car uses brakes to slow down and ensure a safer ride, our immune system also has built-in brakes that continuously work to ensure that our immune responses are adequately slowed down for preserving long-term immunity to pathogens, tumors and vaccines. Long-lived immunity is a hallmark of vertebrate immune systems and is endowed by immune memory cells that persist for the lifetime of an individual following vaccinations or past infections. Immune memory cells are poised to rapidly expand and elaborate effector functions upon reinfection and yet exist in a functionally quiescent state. The data presented in my seminar from our recent work will provide a deeper understanding of immunological brakes, more specifically through Regulatory T cells (Treg), in generation and maintenance of immunological memory in a quiescent state. The role of Treg cells as canonical immunological brakes in preventing autoimmunity and regulating antigen-driven T cell immunity is well established. Here, we show that a specific loss of Treg cells resulted in a loss of quiescence in memory cells. At a molecular level, loss of Treg cells led to an activation of genome-wide transcriptional program that is characteristic of activated effector T cells, which drove transitioning as well as established memory CD8 T cells toward terminally differentiated phenotype, with compromised metabolic fitness, longevity, polyfunctionality, and protective efficacy. This redefines a prevailing paradigm that memory T cells remain inactive due to lack of T cell receptor stimuli and no other factors were thought to contribute to the quiescence of memory T cells. We further identify that Treg cells promote CD8 T cell quiescence, memory function, and longevity under conditions of antigen clearance, through the CTLA-4-CD28-B7 axis. Our studies present the CTLA-4-CD28-CD80/CD86 axis as a potential therapeutic target to accelerate vaccine-induced immunity and improve T cell memory quality in current cancer immunotherapies proposing transient Treg cell ablation.