Chikungunya virus (CHIKV) infection is a reemerging pandemic human arboviral disease. CD4⁺ T cells were previously shown to contribute to joint inflammation in the course of CHIKV infection in mice. The JES6-1 anti-IL-2 antibody selectively expands mouse regulatory T cells (Tregs) by forming a complex with IL-2. In this study, we show that the IL-2 JES6-1-mediated expansion of Tregs ameliorates CHIKV-induced joint pathology. It does so by inhibiting the infiltration of CD4⁺ T cells due to the induction of anergy in CHIKV-specific CD4⁺ effector T cells. These findings suggest that activation of Tregs could also become an alternative approach to control CHIKV-mediated disease.

IMPORTANCE Chikungunya virus (CHIKV) has reemerged as a pathogen of global significance. Patients infected with CHIKV suffer from incapacitating joint pain that severely affects their daily functioning. Despite the best efforts, treatment is still inadequate. While T cell-mediated immunopathology in CHIKV infections has been reported, the role of regulatory T cells (Tregs) has not been explored. The JES6-1 anti-interleukin 2 (IL-2) antibody has been demonstrated to selectively expand mouse Tregs by forming a complex with IL-2. We reveal here that IL-2 JES6-1-mediated expansion of Tregs ameliorates CHIKV-induced joint pathology in mice by neutralizing virus-specific CD4⁺ effector T (Teff) cells. We show that this treatment abrogates the infiltration of pathogenic CD4⁺ T cells through induction of anergy in CHIKV-specific CD4⁺ Teff cells. This is the first evidence where the role of Tregs is demonstrated in CHIKV pathogenesis, and its expansion could control virus-mediated immunopathology.