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

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. CCR5deficient 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.

CCR 5 deficiency/ CCR 5Δ32: resistant to HIV infection at the cost of curtailed CD 4 + T cell memory responses

“…Notably, the formation of TCR nanoclusters was also impaired in lymphoblasts of homozygous ccr5Δ32 individuals, which is concomitant with enhanced levels of ceramide synthase 2 mRNA and saturated ceramide species. Collectively, this elegant study by Martín‐Leal et al () reveals that CCR5 signaling barely affects memory CD4 + T cell differentiation, but facilitates TCR nanoclustering and ameliorates the antigenic sensitivity and memory CD4 + T cell activation upon antigen re‐encounter. Consequently, homozygous ccr5Δ32 individuals may benefit from being resistant to HIV infection at the cost of curtailed CD4 + T cell memory and, potentially, T cell‐dependent humoral responses.…”

“…In this issue of The EMBO Journal , Martín‐Leal et al () describe that CCR5 deficiency in mice leads to an impaired CD4 + T cell memory response. They observed in an OVA‐encoding vaccinia virus model that less antigen‐specific CD4 + memory T cells produced IFNγ in response to antigenic re‐stimulation if mice were deficient for CCR5.…”

“…These data suggest that CCR5 does not hamper memory development itself, but rather affects the strength of the TCR signal or the TCR's sensitivity to antigens and consequently activation of memory T cells. Indeed, Martín‐Leal et al () discovered that CCR5 signaling enables the TCR to form nanoclusters on antigen‐experienced CD4 + T cells, but not on naïve cells (Fig ). Electron microscopy analysis clearly revealed a significant increase in number and size of TCR nanoclusters in CCR5‐proficient antigen‐experienced CD4 + T cells compared to CCR5‐deficient cells.…”

“…Notably, chemokine receptor clustering or oligomerization, promoted by modulated cholesterol levels, was found to enable the integration of distinct signaling pathways of CCR7 required for efficient DC and effector T cell migration (Hauser et al , ; Legler et al , ). Martín‐Leal et al () uncovered that specific ceramide synthases are transcriptionally upregulated in CCR5‐deficient lymphoblasts and that ceramide levels control TCR nanoclustering in these cells (Fig ). An increased nuclear level of the phosphorylated and active form of the transcription factor GATA‐1 in CCR5‐deficient lymphoblasts suggests that CCR5 signaling reduces ceramide levels in antigen‐experienced CD4 + T cells by limiting GATA‐1‐driven transcription of ceramide synthases.…”

Association of HLA and Mutated CCR5 With the Clinical Course of the Disease in Subjects With mild / moderate disease following COVID-19 infection

“…CCR5 is known to play decisive roles as a chemotactic receptor abundantly expressed on monocytes, macrophages and T-cells and its heterozygous mutation related de ciency implies impaired memory CD4 + T-cell response 5 . Thus, in regard to the COVID-19 clinical course the roles of CCR5 (1) within the oral-pharyngeal immune system as the rst line of antiviral immune defense and (2) as a critical receptor governing adaptively induced T-cell memory provide a compelling immune-mechanistic rationale for the putative association of the delta32 near-loss-of-function mutation of CCR5 with altered susceptibility to SARS-CoV-2 infection and COVID-19 morbidity [6][7][8][9] .…”