Mechanisms of T Cell Memory Quiescence

ABSTRACT (COVID-19 SUPPLEMENTAL RESEARCH) During fast-spreading disease outbreaks (such as the present COVID-19 pandemic), quick induction ofherd immunity through vaccination is critical. Currently there are many SARS-CoV2 candidate vaccines invarious stages of clinical development, aimed at inducing robust multimodal protective immunity comprisingboth long-lived antibody and memory T cells. However, we have little control over how quickly protectiveimmunity may be established following immunization. At the very minimum, vaccine-induced T cells require aperiod of ~20-30 days of antigenic rest after initial immunization to effectively downregulate their effectorprogram and convert into quiescent, functionally potent, long-lived memory cells poised at portals of pathogenentry. If vaccine-induced T cells are re-exposed to antigen during this mandatory rest period - as might occurin case of exposure to virulent pathogen during an outbreak - the quantity, quality and overall protectiveefficacy of immune memory are significantly jeopardized. Hence, shortening the window of immune memorydevelopment is a key goal during vaccination, and is of high significance during pandemics to establishaccelerated protection in frontline healthcare and essential service providers, and speed up herd immunity inthe general population for expedited return to normalcy and economic growth.In this administrative supplement, we will evaluate candidate immunomodulatory strategies to accelerate andenhance 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 promotingeffector-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 ableto fully supplement the function of Tregs in memory differentiation, and accelerates the formation of protectiveanti-viral immunity by promoting the metabolic switch necessary for effector-to-memory conversion. Theseproof-of-concept studies in models of viral immunity (conducted under the aegis of past R21, and parent R01awards) lay a strong foundation for enhancing SARS-CoV2-specific immune memory following immunizationwith candidate SARS-CoV2 vaccine in preclinical murine model. These studies represent a naturaltranslational extension of the parent R01 focused on mechanistic and molecular details of Treg-dependentmemory enhancement through CTLA4 in model viral infections. Importantly, CTLA4-Ig is FDA-approved PhaseIII drug - ready for clinical translation. Therefore, immediate impact on our ability to quickly establish herdimmunity against SARS-CoV2 is expected. In addition to addressing the current COVID-19 exigency, thesestudies are also relevant to other pandemics and situations of urgent vaccination of our defense troops forquick deployment to disease endemic areas.