CCR5 deficiency/CCR5Δ32: resistant to HIV infection at the cost of curtailed CD4+ T cell memory responses

Abstract

Orchestrated trafficking and activation by pathogen-derived peptides define the ability of CD4⁺ T helper cells to contribute to an effective adaptive immunity. In this issue of The EMBO Journal, Martín-Leal et al show that the inflammatory chemokine receptor CCR5, well known for its role in cell migration and HIV infection, regulates ceramide synthesis and TCR nanoclustering to promote memory CD4⁺ T cell activation.

Figure 1. CCR5 signaling dampens ceramide synthesis to enable TCR nanoclustering in antigen‐experienced CD4⁺ T cells

G_i protein‐dependent CCR5 signaling in antigen‐experienced, but not in naïve CD4⁺ T cells, correlates with reduced GATA‐1‐mediated transcription of ceramide synthase 2 (CerS2) and production of ceramide species. Lowering ceramide levels in the plasma membrane of lymphoblasts enables TCR nanoclustering, which in turn increases the antigenic sensitivity of the TCR and ameliorates CD4⁺ T‐cell–B‐cell cooperation in humoral responses upon antigen re‐encounter. Lymphoblasts of CCR5‐deficient mice or homozygous CCR5Δ32 human individuals fail to down‐modulate ceramide levels required for TCR nanoclustering.