CCR5 deficiency impairs CD4(+) T‐cell memory responses and antigenic sensitivity through increased ceramide synthesis

CCR5 is not only a coreceptor for HIV‐1 infection in CD4(+) T cells, but also contributes to their functional fitness. Here, we show that by limiting transcription of specific ceramide synthases, CCR5 signaling reduces ceramide levels and thereby increases T‐cell antigen receptor (TCR) nanoclustering in antigen‐experienced mouse and human CD4(+) T cells. This activity is CCR5‐specific and independent of CCR5 co‐stimulatory activity. CCR5‐deficient mice showed reduced production of high‐affinity class‐switched antibodies, but only after antigen rechallenge, which implies an impaired memory CD4(+) T‐cell response. This study identifies a CCR5 function in the generation of CD4(+) T‐cell memory responses and establishes an antigen‐independent mechanism that regulates TCR nanoclustering by altering specific lipid species.