Identification of a TCR signature in peripheral blood derived CD4+ T cells, associated with chronic chikungunya disease, suggests a conducive, female-biased, background immune profile

Introduction Chronic chikungunya disease (CCD) is characterized by persistent inflammatory joint pains following acute chikungunya virus (CHIKV) infection in about half of the patients . CD4 + T cells have been implicated in CCD pathogenesis, yet disease-associated T cell receptor (TCR) signatures remain undefined. Methods Peripheral blood CD4 + T cells were collected from 65 Cambodian participants six months after RTqPCR–confirmed CHIKV infection during the 2020 outbreak, including chronic (n=16), non-chronic (n=16), and control (n=33) individuals. TCR α, β, γ, and δ CDR3 regions were sequenced and clustered using ClusTCR. Differential enrichment was assessed by Fisher’s exact test. L1-regularized logistic regression incorporating age, gender, and TCR clone counts was used to identify non-redundant TCR signatures. Results Eight TCR clusters were differentially enriched between chronic and non-chronic patients. Chronic disease was associated with increased TRAV9-2 and TRAV41.2 and decreased TRAV41.3 and TRBV18 clone counts. Female controls exhibited higher baseline TRAV9-2 frequencies, suggesting a pre-existing, female-biased immune background associated with CCD susceptibility. Discussion A distinct CD4 + TCR signature detectable six months post-infection characterizes patients who develop CCD. The association of TRAV9-2 with chronic disease and its enrichment in females suggests an underlying immune predisposition rather than persistent virus-driven expansion. These findings support a role for CD4 + T cells in CCD pathophysiology and identify candidate TCR-based biomarkers for disease risk stratification.