CD69: from activation marker to metabolic gatekeeper

Abstract

CD69 is a membrane-bound, type II C-lectin receptor. It is a classical early marker of lymphocyte activation due to its rapid appearance on the surface of the plasma membrane after stimulation. CD69 is expressed by several subsets of tissue resident immune cells, including resident memory T (TRM) cells and gamma delta (γδ) T cells, and is therefore considered a marker of tissue retention. Recent evidence has revealed that CD69 regulates some specific functions of selected T-cell subsets, determining the migration-retention ratio as well as the acquisition of effector or regulatory phenotypes. Specifically, CD69 regulates the differentiation of regulatory T (Treg) cells as well as the secretion of IFN-γ, IL-17, and IL-22. The identification of putative CD69 ligands, such as Galectin-1 (Gal-1), suggests that CD69-induced signaling can be regulated not only during cognate contacts between T cells and antigen-presenting cells in lymphoid organs, but also in the periphery, where cytokines and other metabolites control the final outcome of the immune response. Here, we will discuss new aspects of the molecular signaling mediated by CD69 and its involvement in the metabolic reprogramming regulating TH-effector lineages.

Keywords: CD69; Galectin-1; LAT1; Metabolism; S1P1; T cells; mTOR.

Figure 1. CD69 counteracts S1P1 signaling that favors TH1/TH17 polarization.

Cartoon showing intracellular signaling associated to the expression of S1P1 on the membrane. The binding of S1P to S1P1 receptor increases mTOR/HIF-1α activation as well as increase of JAK2/pSTAT3 pathway. Both signaling routes increase TH1/TH17 effector phenotype and prevent Treg-cell differentiation. CD69 expression in activated lymphocytes prevents S1P1-induced signaling by promoting the internalization and degradation of the receptor (1) and by increasing the JAK3/pSTAT5 pathway (2), which counteract STAT3-induced expression of IL-17 and promotes Treg development. The interaction of CD69 with putative ligands, for example Gal-1 (soluble, bound to the plasma membrane of dendritic cells, either directly or through an unidentified, glycosylated, co-receptor) could potentially modulate these CD69-mediated effects.

Figure 2. Lateral association of CD69 with the amino acid transporter LAT1-CD98 complex regulates TH1/TH17/Treg balance.

Cartoon depicts the lateral interactions of CD69 with the LAT1-CD98 amino acid transporter complex. CD69 increase Trp transport through LAT1-CD98 and favors AHR activation through binding of the Trp-derived FICZ ligand. Activation of AHR-transcriptional activity favors IL-22 secretion. Amino acid uptake through CD69/LAT1-CD98 complex also favors mTOR activation, which promotes TH1 and TH17 development and prevents Treg-cell differentiation. mTOR also controls HIF-1α, which negatively regulates Treg-cell function by promoting Foxp3 degradation. AHR expression attenuates HIF-1α-mediated effects and modulates the TH-phenotype of effector T cells.