Endogenous retroviruses in autoimmunity: T cell repertoire, tolerance, and disease - PROJECT SUMMARY Rheumatoid Arthritis (RA) is a chronic, destructive autoimmune disease that primarily targets joints. It affects millions globally and is associated with both disability and reduced lifespan. Antigen-dependent activation of CD4 T cells contributes to disease onset. However, the specific antigens that activate CD4 T cells and the mechanisms by which they evade tolerance remain undefined. Therefore, our long-term goal is to identify the earliest events that activate self-reactive T cells and define the mechanisms they employ to subvert tolerance. This knowledge may reveal vulnerabilities in disease-causing T cells that could lead to new diagnostic and therapeutic interventions. To identify the early mechanistic events that break T cell tolerance, we use the SKG mouse model in which a hypomorphic Zap70 kinase allele impairs TCR signaling; this deficit allows autoreactive thymocytes to escape negative selection, leading to mature autoreactive T cells that cause autoimmune arthritis resembling RA. Our group identified a subset of highly arthritogenic CD4 T cells in these mice. This subset of CD4 T cells is enriched for T cells that recognize superantigens (Sags) from an endogenous retrovirus (ERV) known as the mouse mammary tumor virus (MMTV). ERVs are implicated in human autoimmune disease, but determining their causal role has been exceptionally difficult. Our preliminary data indicate that these Sag-reactive T cells, which are normally deleted in the thymus of wild-type mice, escape deletion in SKG mice, accumulate in arthritic joints, and contribute to disease pathogenesis. These findings suggest that ERVs may play a crucial role in initiating and sustaining autoimmune responses. Furthermore, we find a similar process may be occurring in human RA synovial tissue. The central hypothesis of this proposal is that ERV Sags break immune tolerance and drive RA by persistently engaging and activating self-reactive T cells. To test this, we will use genetic engineering to create and study Sag-reactive CD4 T cells in both SKG and wild-type mice, assessing their role in arthritis initiation and analyzing their activation states and clonality through single-cell sequencing. Parallel human studies will explore the TCR repertoire and transcriptomes in RA synovial T cells. Additionally, we will eliminate MMTV Sags in SKG mice to examine their effects on T cell development, activation, tolerance mechanisms, and arthritis progression, providing insights into the influence of ERVs on central and peripheral tolerance. This research will elucidate how ERVs and their Sags influence T cell activation and tolerance, potentially leading to new therapeutic strategies for RA and related autoimmune diseases.
