Unconventional Repertoire Profile Is Imprinted during Acute Chikungunya Infection for Natural Killer Cells Polarization toward Cytotoxicity

Abstract

Chikungunya virus (CHIKV) is a worldwide emerging pathogen. In humans it causes a syndrome characterized by high fever, polyarthritis, and in some cases lethal encephalitis. Growing evidence indicates that the innate immune response plays a role in controlling CHIKV infection. We show here that CHIKV induces major but transient modifications in NK-cell phenotype and function soon after the onset of acute infection. We report a transient clonal expansion of NK cells that coexpress CD94/NKG2C and inhibitory receptors for HLA-C1 alleles and are correlated with the viral load. Functional tests reveal cytolytic capacity driven by NK cells in the absence of exogenous signals and severely impaired IFN-γ production. Collectively these data provide insight into the role of this unique subset of NK cells in controlling CHIKV infection by subset-specific expansion in response to acute infection, followed by a contraction phase after viral clearance. Chikungunya virus (CHIKV) infection, which is responsible for devastating human illness, is rapidly becoming a global concern. The spread of this disease throughout tropical areas, where it now affects nearly 40 countries, underlines the need to improve our understanding of this infection. In 2008, CHIKV was listed as a US National Institute of Allergy and Infectious Disease (NIAID) category C priority pathogen. Natural killer (NK) cells are cytotoxic effector cells that play a vital role in the innate immune system by limiting acute infection, as previously described for several other diseases. This report describes the first phenotypic and functional analysis of NK cells soon after infection by this virus. The key element of this study was the detailed analysis of the expansion of NK cells. Coexpression of NKG2C activating receptors and HLA-C1 ligands is associated with viral load, impaired IFN-γ production, and significant cytolytic functions. We found that NK cells were able to sense CHIKV from the beginning of infection and contributed to the clearance of the infected cells through the expansion of a unique NK-cell subset.