Inflammation and Lymphopenia Trigger Autoimmunity by Suppression of IL-2-Controlled Regulatory T Cell and Increase of IL-21-Mediated Effector T Cell Expansion

The dynamic interplay between regulatory T cells (T-regs) and effector T cells (T-effs) governs the balance between tolerance and effector immune responses. Perturbations of T-reg frequency and function or imbalances in T-reg/T-eff levels are associated with the development of autoimmunity. The factors that mediate these changes remain poorly understood and were investigated in this study in murine autoimmune arthritis. T-regs displayed a stable phenotype in arthritic mice and were fully functional in in vitro suppression assays. However, their expansion was delayed relative to T-effs (T follicular helper cells and Th17 cells) during the early stages of autoimmune reactivity. This imbalance is likely to have led to insufficient T-reg control of T-effs and induced autoimmunity. Moreover, a counterregulatory and probably IL-7-driven increase in thymic T-reg production and recruitment to inflamed tissues was too slow for disease prevention. Increased T-eff over T-reg expansion was further aggravated by inflammation and lymphopenia. Both these conditions contribute to autoimmune pathogenesis and were accompanied by decreases in the availability of IL-2 and increases in levels of IL-21. IL-2 neutralization or supplementation was used to show that T-reg expansion mainly depended on this cytokine. IL-21R(-/-) cells were used to demonstrate that IL-21 promoted the maintenance of T-effs. Thus, at inflammatory sites in experimental arthritis, a deficit in IL-2 hampers T-reg proliferation, whereas exaggerated IL-21 levels overwhelm T-reg control by supporting T-eff expansion. This identifies IL-2 and IL-21 as targets for manipulation in therapies for autoimmunity.