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.