<scp>CCR</scp> 5 deficiency impairs <scp>CD</scp> 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.
We thank D Sancho and JW Yewdell for rVACV‐OVA virus, RM Peregil for technical assistance, MC Moreno and S Escudero for flow cytometry services (CNB), MT Rejas and M Guerra for EM service (CBM‐SO), and C Mark for excellent editorial assistance. Fundació ACE would like to thank patients, controls, and the staff who participated in this project. This work was funded by grants from the Spanish Ministerio de Ciencia, Innovación y Universidades (SAF2017–83732‐R to SM; FIS2016‐78883‐C2‐2‐P to MC; CTQ2017‐85378‐R; AEI/FEDER, EU), the Instituto de Salud Carlos III (ISCIII) (PI13/02434, PI16/01861 to AR), the Comunidad de Madrid (B2017/BMD‐3733; IMMUNOTHERCAN‐CM to SM), and the Merck‐Salud Foundation (to SM). WWS and CD were supported by the Deutsche Forschungsgemeinschaft (DFG) through BIOSS‐EXC294 and CIBSS‐EXC 2189 (Project 390939984), SCHA976/7‐1, and SFB1381. The Genome Research @ Fundació ACE project (GR@ACE) is supported by the Fundación Bancaria La Caixa, Grifols SA, Fundació ACE, and ISCIII (Ministry of Health, Spain). Fundació ACE is a participating center in the Dementia Genetics Spanish Consortium (DEGESCO).