Mechanisms of T Cell Memory Quiescence

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ABSTRACT (COVID-19 SUPPLEMENTAL RESEARCH) During fast-spreading disease outbreaks (such as the present COVID-19 pandemic), quick induction of herd immunity through vaccination is critical. Currently there are many SARS-CoV2 candidate vaccines in various stages of clinical development, aimed at inducing robust multimodal protective immunity comprising both long-lived antibody and memory T cells. However, we have little control over how quickly protective immunity may be established following immunization. At the very minimum, vaccine-induced T cells require a period of ~20-30 days of antigenic rest after initial immunization to effectively downregulate their effector program and convert into quiescent, functionally potent, long-lived memory cells poised at portals of pathogen entry. If vaccine-induced T cells are re-exposed to antigen during this mandatory rest period – as might occur in case of exposure to virulent pathogen during an outbreak – the quantity, quality and overall protective efficacy of immune memory are significantly jeopardized. Hence, shortening the window of immune memory development is a key goal during vaccination, and is of high significance during pandemics to establish accelerated protection in frontline healthcare and essential service providers, and speed up herd immunity in the general population for expedited return to normalcy and economic growth. In this administrative supplement, we will evaluate candidate immunomodulatory strategies to accelerate and enhance vaccine-induced protective T cell memory to SARS-CoV2 by facilitating Treg-aided effector-to- memory conversion. This work is based on our studies establishing a critical role of Tregs in promoting effector-to-memory conversion through CTLA4, an inhibitory molecule most highly expressed on Tregs (amongst all immune cells) (Immunity, 2015). Importantly, soluble CTLA4 administered in trans, is alone able to fully supplement the function of Tregs in memory differentiation, and accelerates the formation of protective anti-viral immunity by promoting the metabolic switch necessary for effector-to-memory conversion. These proof-of-concept studies in models of viral immunity (conducted under the aegis of past R21, and parent R01 awards) lay a strong foundation for enhancing SARS-CoV2-specific immune memory following immunization with candidate SARS-CoV2 vaccine in preclinical murine model. These studies represent a natural translational extension of the parent R01 focused on mechanistic and molecular details of Treg-dependent memory enhancement through CTLA4 in model viral infections. Importantly, CTLA4-Ig is FDA-approved Phase III drug – ready for clinical translation. Therefore, immediate impact on our ability to quickly establish herd immunity against SARS-CoV2 is expected. In addition to addressing the current COVID-19 exigency, these studies are also relevant to other pandemics and situations of urgent vaccination of our defense troops for quick deployment to disease endemic areas.