A Pathogenic Role for CD4+ T Cells during Chikungunya Virus Infection in Mice

Abstract

Chikungunya virus (CHIKV) is an alphavirus that causes chronic and incapacitating arthralgia in humans. Injury to the joint is believed to occur because of viral and host immune-mediated effects. However, the exact involvement of the different immune mediators in CHIKV-induced pathogenesis is unknown. In this study, we assessed the roles of T cells in primary CHIKV infection, virus replication and dissemination, and virus persistence, as well as in the mediation of disease severity in adult RAG2−/−, CD4−/−, CD8−/−, and wild-type CHIKV C57BL/6J mice and in wild-type mice depleted of CD4+ or CD8+ T cells after Ab treatment. CHIKV-specific T cells in the spleen and footpad were investigated using IFN-γ ELISPOT. Interestingly, our results indicated that CHIKV-specific CD4+, but not CD8+, T cells are essential for the development of joint swelling without any effect on virus replication and dissemination. Infection in IFN-γ−/− mice demonstrated that pathogenic CD4+ T cells do not mediate inflammation via an IFN-γ–mediated pathway. Taken together, these observations strongly indicate that mechanisms of joint pathology induced by CHIKV in mice resemble those in humans and differ from infections caused by other arthritogenic viruses, such as Ross River virus.

Attenuated and vectored vaccines protect nonhuman primates against Chikungunya virus

“…Thus, it was of importance to assess the individual merits of new CHIKV vaccine platforms in a more stringent animal model that more closely resembles a clinical setting. Antibody responses are known to correlate with protection against CHIKV (29)(30)(31)(32)(33)(34)(35)(36), but CD4 T cell responses may also be important (37)(38)(39). Thus, it was of importance to determine the potential immunological differences that our vaccine candidate might display.…”

Chikungunya and Its Interaction With the Host Cell

“…Disease signs and symptoms following infection with CHIKV have been associated with CHIKV infection of cells in musculoskeletal tissues, such as fibroblasts and osteoblasts, and infiltration of inflammatory cells-consisting predominantly of monocytes, macrophages, natural killer cells, and T cells-in musculoskeletal tissues. Recent works have demonstrated that mice lacking mature T and B cells and mice lacking CD4 + T cells had reduced joint swelling and less severe musculoskeletal tissue injury during the acute stage of CHIKV disease, suggesting a pathogenic role for CD4 + T cells in CHIKV disease [80,81].…”

Chikungunya: Molecular Aspects, Clinical Outcomes and Pathogenesis

“…In the infection by Alphavirus, an increase has been found in the activation of T CD4+ lymphocytes 54,71 , which differentiate to Th17 and infiltrate the synovial space, possibly promoting local inflammation 72 .…”