Rheumatoid arthritis (RA) is a debilitating disease that causes inflammation and deforming joint destruction. RA afflicts 1.5 million people in the United States and is becoming increasingly more prevalent in the veteran community as this population ages. It is also one of the most expensive illnesses to treat, resulting in hundreds of millions of dollars in increased health care spending by the Veteran Administration (VA). The underlying cause of RA remains unclear. Infections driving a misdirected response to self-proteins has been hypothesized to underlie RA and other autoimmune diseases, but why some people remain healthy whereas others develop autoimmunity remain poorly understood. Using SARS-CoV-2 infection as a model, we will investigate RA- related differences in immune composition before exposure and determine how it responds to infection. The proposed study will test the overarching hypothesis that disrupted interaction with the microbiome in RA patients amplifies cross-reactive SARS-CoV-2-specific T cells at baseline, which contributes to broadening of T cell and antibody responses after SARS-CoV-2 infection. In Aim 1, we will determine how pre-existing cross-reactive responses change in patients with RA. We have recently demonstrated that CD4+ T cells from healthy adults are capable of recognizing SARS-CoV-2 prior to exposure. Further, a subset of SARS-CoV-2 specific precursors respond to commensal bacteria. Building on this, we will determine if the basal level of T cell cross-reactivity becomes amplified in an autoimmune setting. In Aim 2, we will determine how COVID-19 impacts cross-reactive responses. We will test if infection drives further expansion of cross- reactive T cells in RA patients and define the relationship between the breadth of CD4+ T cells and antibody responses. Data generated from these experiments will provide vital knowledge on SARS-CoV-2 specific T cells and address fundamental questions on cross-reactive responses in humans. These findings will likely be relevant beyond SARS-CoV-2 to inform cross-reactive responses to other pathogens.