CCR5 deficiency impairs CD4+ T-cell memory responses and antigenic sensitivity through increased ceramide synthesis.

Martín-Leal, AnaBlanco, RaquelCasas, JosefinaSáez, María ERodríguez-Bovolenta, Elenade Rojas, ItziarDrechsler, CarinaReal, Luis MiguelFabrias, GemmaRuíz, AgustínCastro, MarioSchamel, Wolfgang WaAlarcón, Balbinovan Santen, Hisse MMañes, Santos2023-02-092023-02-092020-06-11http://hdl.handle.net/10668/15719CCR5 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.enAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/T-cell receptorccr5[delta]32humoral responsemembrane phasesphingolipidAnimalsAntigensCD4-Positive T-LymphocytesCeramidesHEK293 CellsHumansImmunologic MemoryMiceMice, KnockoutReceptors, CCR5CCR5 deficiency impairs CD4+ T-cell memory responses and antigenic sensitivity through increased ceramide synthesis.research article32525588open access10.15252/embj.20201047491460-2075PMC7396835https://doi.org/10.15252/embj.2020104749https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396835/pdf