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

EMBO J. 2020 Aug 3;39(15):e104749. doi: 10.15252/embj.2020104749. Epub 2020 Jun 11.

Abstract

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.

Keywords: T-cell receptor; ccr5[delta]32; humoral response; membrane phase; sphingolipid.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens / genetics
  • Antigens / immunology*
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / immunology*
  • Ceramides / genetics
  • Ceramides / immunology*
  • HEK293 Cells
  • Humans
  • Immunologic Memory*
  • Mice
  • Mice, Knockout
  • Receptors, CCR5 / deficiency*
  • Receptors, CCR5 / immunology

Substances

  • Antigens
  • CCR5 protein, human
  • CCR5 protein, mouse
  • Ceramides
  • Receptors, CCR5