CCR5 deficiency impairs CD4+ T cell memory responses and antigenic sensitivity through increased ceramide synthesis
Martin, A.; Blanco, R.; Casas, J.; Saez, M. E.; Rodriguez-Bovolenta, E.; de Rojas, I. E.; Drechsler, C.; Real, L. M.; Fabrias, G.; Ruiz, A.; Castro, M.; Schamel, W. W. A.; Alarcon, B.; van Santen, H. M.; Manes, S.
Show abstract
In CD4+ T cells, CCR5 is not only a coreceptor for HIV-1 infection, but also contributes to their functional fitness. Here we show that by limiting GATA-1-induced 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 costimulatory 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.
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