The Chemokine Receptor CCR5 Links Memory CD4+ T Cell Metabolism to T Cell Antigen Receptor Nanoclustering.

Raquel Blanco,Marta Gómez De Cedrón,Laura Gámez-Reche,Rosa A Lacalle,Ana Martín-Leal,Ana Ramírez De Molina,Santos Mañes,Alicia González-Martín

doi:10.3389/fimmu.2021.722320

Abstract

The inhibition of anabolic pathways, such as aerobic glycolysis, is a metabolic cornerstone of memory T cell differentiation and function. However, the signals that hamper these anabolic pathways are not completely known. Recent evidence pinpoints the chemokine receptor CCR5 as an important player in CD4+ T cell memory responses by regulating T cell antigen receptor (TCR) nanoclustering in an antigen-independent manner. This paper reports that CCR5 specifically restrains aerobic glycolysis in memory-like CD4+ T cells, but not in effector CD4+ T cells. CCR5-deficient memory CD4+ T cells thus show an abnormally high glycolytic/oxidative metabolism ratio. No CCR5-dependent change in glucose uptake nor in the expression of the main glucose transporters was detected in any of the examined cell types, although CCR5-deficient memory cells did show increased expression of the hexokinase 2 and pyruvate kinase M2 isoforms, plus the concomitant downregulation of Bcl-6, a transcriptional repressor of these key glycolytic enzymes. Further, the TCR nanoclustering defects observed in CCR5-deficient antigen-experienced CD4+ T cells were partially reversed by incubation with 2-deoxyglucose (2-DG), suggesting a link between inhibition of the glycolytic pathway and TCR nanoscopic organization. Indeed, the treatment of CCR5-deficient lymphoblasts with 2-DG enhanced IL-2 production after antigen re-stimulation. These results identify CCR5 as an important regulator of the metabolic fitness of memory CD4+ T cells, and reveal an unexpected link between T cell metabolism and TCR organization with potential influence on the response of memory T cells upon antigen re-encounter.

Highlights

The adaptive immune system has the ability to generate immunological memory
To analyze whether chemokine receptor 5 (CCR5) affects the metabolic reprogramming of CD4+ T cells, WT and CCR5-/- OT-II splenocytes were stimulated with cognate antigen and subsequently cultured for four days in the presence of IL-2 or IL-15, but in the absence of antigenic stimulation (Figure 1A)
No differences were seen between any cell type in terms of basal or maximum oxygen consumption rate (OCR) (OCRmax), spare respiratory capacity (SRC; a variable determining the capacity of the cell to respond to an energy demand), or ATP production (Supplementary Figure S2)

Summary

Introduction

The adaptive immune system has the ability to generate immunological memory. This allows for rapid and robust secondary responses upon antigen re-encounter [1]. The response of memory T (TM) cells to low antigen concentrations has been linked to the antigen-independent formation of T cell antigen receptor (TCR) oligomers known as nanoclusters [2,3,4]. The nanoscopic organization of the TCR molecules is not exclusive to TM cells; it occurs in effector T (TE) cells, to a lesser extent. TCR nanoscopic organization allows cooperativity between TCR molecules [7] and increases avidity for multimeric peptide-major histocompatibility complexes [5, 8]. TCR nanoclustering in antigen-experienced TM and TE lymphoblasts is strongly dependent on the sterol and sphingolipid composition of the plasma membrane [6, 9, 10]; the importance of the cell’s metabolic state in TCR organization has, been left completely unexplored

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Conclusion