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

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.