Protective and Pathogenic T Cells Responding to SARS-CoV-2 in Health and Disease

SUMMARY Understanding the adaptive response to SARS-CoV-2 is critical to halting the devastation wreaked by the COVID-19 pandemic, by identifying new drug targets and informing the rational design of vaccines. Common coronaviruses and human rhinovirus (RV) both cause common cold, and multiple strains of each exist that have varying degrees of sequence identity. All humans, and adults in particular, possess antigen-experienced immune cells by virtue of frequent viral infections. Our work using experimental infections with RV in man has provided unprecedented insight into adaptive immunity to this relatively benign, but troublesome, virus. Seminal findings include a pivotal role for the rapid mobilization of cross-reactive memory T helper 1 (Th1) cells and T-bet+ B cells in controlling RV infection. Th1 cells are critical to anti-viral responses by aiding in viral clearance through secretion of IFN-γ, and providing help to B cells for the production of neutralizing antibodies. Notably, expansion of circulating RV-specific Th1 cells is limited to those infected patients who develop serum neutralizing antibodies, whereas this feature is lacking in those who are infected but fail to mount an antibody response. Nonetheless, there is also evidence of a pathogenic role for virus-specific Th1 cells in patients with asthma who are at risk of adverse sequelae, based on enhanced and persistent responses. We posit that a similar scenario underlies the "cytokine storm" and rapid decline in patients with severe COVID-19 and those who are at risk, thereby reflecting the double-edged sword of Th1 cells in anti-viral immunity. The technological tools and analytical pipelines developed to study cross-strain immunity to RV infections, coupled with access to COVID-19 patients and those at risk, allow us to pivot quickly to analyze T cell responses to SARS-CoV-2. Powerful single-cell analytical tools for interrogating large cell numbers will be used to test the theory that cross-reactive T cells respond rapidly to SARS-CoV-2, and their numbers and functional attributes determine disease status in healthy individuals and at-risk patients. Based on our expertise, we are uniquely poised to map CD4+ T cell epitopes across the SARS-CoV-2 proteome. These data will be used to generate MHCII/peptide tetramers to detect and phenotype cross-reactive SARS-CoV-2-specific memory CD4+ T cells that pre-exist in uninfected adults and persist in recovered COVID-19 patients. This will establish proof-of- concept for priming of T cells for rapid response by previous exposures to related coronavirus strains (Aim 1). Next, novel computational tools and tetramers will be used to identify hallmarks of overactive virus-specific T cells in hospitalized COVID-19 patients in the acute phase, and to assess immune paralysis and antibody deficiencies in those who develop respiratory failure (Aim 2). Finally, we will confirm in vivo expansion of virus- specific pathogenic Th1 cells in uninfected asthmatics with severe disease, and boosting of their function by pro-inflammatory cues present in the lower airways (Aim 3). Study outcomes will yield new insight into T cell mechanisms of viral pathogenesis, and aid in vaccine design and monitoring for COVID-19.