Abstract
Abstract
Recruitment of diverse antigen-specific T-cell clones is essential for effective CD4+ T cell immunity, enhancing the robustness of responses to antigenic variation. However, because CD4+ T cell proliferation requires repeated antigen encounter1,2 and peptide–MHC-II complexes are long-lived in vivo3, sustained stimulation is expected to preferentially expand the clones with the highest TCR avidity4, thereby reducing clonal diversity. Yet, CD4+ T cell responses in vivo remain remarkably diverse5–8. The mechanisms that preserve clonal diversity during T cell expansion remain poorly understood. Here, we provide in vivo evidence for antigen-specific CD4+ T cell–T cell (T–T) contacts and demonstrate that SOCS1-dependent inhibition of antigen-experienced CD4+ T cell proliferation preserves repertoire diversity during an ongoing immune response. Mathematical modelling predicted that such T–T contacts can maintain a diverse response by limiting preferential expansion of the most avid clones. Inducible SOCS1 disruption validated this prediction by converting the response into an oligoclonal expansion dominated by a few high-avidity clones. Large-scale experimental measurements of TCR avidity and antigen-variant recognition showed that wild-type repertoires retain clones spanning a broad avidity range and complementary cross-reactivity profiles. A sequence-based machine-learning model extended these measurements to whole repertoires, revealing broader coverage of antigenic variation in wild-type than in SOCS1-deficient responses, a prediction confirmed experimentally by recall responses to antigen variants. Simulations further showed that the size of wild-type expanded repertoires lies within the range predicted to achieve near-optimal coverage of antigenic variation. Thus, antigen-specific T cell–T cell interactions and SOCS1 signaling control TCR diversity and improve the adaptability of CD4+ T cell immunity to antigenic variation.