LAUSR

The contribution of low‐affinity T cells to autoimmunity in the context of polyclonal T‐cell responses is understudied due to the limitations in their capture by tetrameric reagents and low level of activation in response to antigenic stimulation. As a result, low‐affinity T cells are often disregarded as nonantigen‐specific cells irrelevant to the immune response. Our study aimed to assess how the level of self‐antigen reactivity shapes T‐cell lineage and effector responses in the context of spontaneous tissue‐specific autoimmunity observed in NOD mice. Using multicolor flow cytometry in combination with Nur77GFP reporter of TCR signaling, we identified a dormant population of T cells that infiltrated the pancreatic islets of prediabetic NOD mice, which exhibited reduced levels of self‐tissue reactivity based on expression of CD5 and Nur77GFP. We showed that these CD5low T cells had a unique TCR repertoire and exhibited low activation and minimal effector function; however, induced rapid diabetes upon transfer. The CD4+CD5low T‐cell population displayed transcriptional signature of central memory T cells, consistent with the ability to acquire effector function post‐transfer. Transcriptional profile of CD5low T cells was similar to T cells expressing a low‐affinity TCR, indicating TCR affinity to be an important factor in shaping CD5low T‐cell phenotype and function at the tissue site. Overall, our study suggests that autoimmune tissue can maintain a reservoir of undifferentiated central memory‐like autoreactive T cells with pathogenic effector potential that might be an important source for effector T cells during long‐term chronic autoimmunity.