Chikungunya virus-specific CD4+ T cells are associated with chronic chikungunya viral arthritic disease in humans

Chikungunya virus (CHIKV) is a mosquito-borne virus that can cause chronic chikungunya virus disease (CHIKVD), which is characterized by persistent incapacitating arthralgia. Despite recurring CHIKV outbreaks and recent approval of a vaccine, the breadth and target of T cell responses in CHIKVD remain largely understudied. Here, we tested peripheral blood mononuclear cells (PBMCs) collected from CHIKV-infected individuals against overlapping peptide pools sequentially spanning the entire CHIKV proteome. We detected robust CHIKV-specific CD4⁺, but not CD8⁺, T cell responses in infected individuals. Individuals with chronic arthralgia displayed significantly higher CD4⁺ T cell responses against nsP1, nsP2, and E2 proteins and exhibited a significantly lower Th1 CD4⁺ T cell population, compared to individuals who had recovered. Additionally, CD4⁺ T cells in chronic individuals were marked by a predominant production of tumor necrosis factor alpha (TNF-α). Overall, our work comprehensively characterizes T cell responses in CHIKVD in humans and provides insights into the role of T cells in CHIKVD.