Ccr5 Deficiency Impairscd4(+)T-Cell Memory Responses And Antigenic Sensitivity Through Increased Ceramide Synthesis

CCR5 is not only a coreceptor forHIV-1 infection inCD4(+)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 humanCD4(+)T cells. This activity isCCR5-specific and independent ofCCR5 co-stimulatory activity.CCR5-deficient mice showed reduced production of high-affinity class-switched antibodies, but only after antigen rechallenge, which implies an impaired memoryCD4(+)T-cell response. This study identifies aCCR5 function in the generation ofCD4(+)T-cell memory responses and establishes an antigen-independent mechanism that regulatesTCRnanoclustering by altering specific lipid species.