CCR 5 deficiency impairs CD 4 + T‐cell memory responses and antigenic sensitivity through increased ceramide synthesis

Abstract

CCR 5 is not only a coreceptor for HIV ‐1 infection in CD 4⁺ T cells, but also contributes to their functional fitness. Here, we show that by limiting transcription of specific ceramide synthases, CCR 5 signaling reduces ceramide levels and thereby increases T‐cell antigen receptor (TCR ) nanoclustering in antigen‐experienced mouse and human CD 4⁺ T cells. This activity is CCR 5‐specific and independent of CCR 5 co‐stimulatory activity. CCR 5‐deficient mice showed reduced production of high‐affinity class‐switched antibodies, but only after antigen rechallenge, which implies an impaired memory CD 4⁺ T‐cell response. This study identifies a CCR 5 function in the generation of CD 4⁺ T‐cell memory responses and establishes an antigen‐independent mechanism that regulates TCR nanoclustering by altering specific lipid species.