A feedback control for restraining autoimmune γδ T cells: reprogramming into ILC1s

γδ T cells are promising mediators of cancer immunotherapy, yet their potential to drive autoimmunity remains incompletely understood. Here, we identify a feedback mechanism in which innate-like Vγ1.1⁺Vδ6.3⁺ T cells are reprogrammed into ILC1-like cells, thereby restraining autoimmune pathology. We define a previously unrecognized ILC1 subset whose development depends on an intact Tcrd locus. These cells predominantly harbor productive Vγ1.1 and Vδ6 rearrangements, consistent with their origin from Vγ1.1⁺Vδ6.3⁺ T cells. Mechanistically, TCR signaling induces Id3, which suppresses E protein-dependent activation of T cell-specific genes, including that encoding Vδ6.3. Id3 ablation drives robust expansion of Vγ1.1⁺Vδ6.3⁺ T cells and severe autoimmunity, characterized by tissue infiltration, autoantibody production, enhanced T follicular helper cell differentiation, and accumulation of germinal center and age-associated B cells. Together with previously described exocrine dysfunction, these features resemble human Sjögren's disease. Consistent with this, we observed in the salivary glands of Sjogren's disease patients an increased frequency of CD4⁻CD8⁻ T cells enriched for γδ T cells, including subsets functionally analogous to murine Vγ1.1⁺Vδ6.3⁺ cells. Collectively, these findings uncover a TCR-Id3-dependent reprogramming pathway that limit the pathogenic potential of harmful γδ T cells.