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 migrationretention 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 r Galectin-1 r LAT1 r Metabolism r mTOR r S1P1 r T cells IntroductionCD69 is a disulfide-linked homodimer protein with two differentially glycosylated subunits (28-32 kDa). Each subunit consists of an extracellular C-type lectin domain (CTLD) connected with a single-spanning transmembrane region followed by a short cytoplasmic tail (Fig. 1). The CD69 gene is located in the natural killer (NK) gene cluster, chromosome 6 in mouse and 12 in human [1,2]. Binding sites for several inducible transcriptional factors such as nuclear factor (NF)-κB, erythroblast transformationspecific related gene-1 (ERG-1) and activator protein-(AP-) 1 are located within the CD69 gene promoter [3,4]. CD69 expression is readily upregulated upon activation in most leukocytes, which underlies its widespread use as a marker of activated lymphocytes and NK cells, mainly [5]. In addition to its intrinsic value as an Correspondence: Dr. Francisco Sánchez-Madrid e-mail: fsmadrid@salud.madrid.org activation marker, recent evidence suggests that CD69 is also an important regulator of immune responses. Although the precise role of CD69 expression on immune cells function is yet to be elucidated, accumulating experimental evidence has revealed that CD69 may determine patterns of cytokine release as well as homing and migration of activated lymphocytes. In this review, we aim to update the state of the art regarding the functional role of CD69 in the regulation of the immune responses. We offer an integrated perspective of the mechanisms that drive the immune effects mediated by CD69 as well as potential synergies and antagonisms with other signaling routes involved in the immune response. CD69 is an early activation markerCD69 expression is rapidly induced on the surface of T lymphocytes after TCR/CD3 engagement, activating cy...

CD28 and CD57 define four populations with distinct phenotypic properties within human CD8+ T cells

“…E). CD69 has been indicated as a marker for T cell activation, and recently, as a molecule involved in cell migration important for T cell homing to lymph nodes and to the BM . When the expression of CD69 was quantified in CD28 + CD57 −, DP, DN, and CD28 − CD57 + CD8 + T cells, it was higher in DP when compared with the other subsets (Fig.…”

Targeting immunotherapy for bladder cancer using anti‐CD3× B7‐H3 bispecific antibody

“…CD69 has been known as an early activation marker of T cells. CD69 expression is rapidly induced on the surface of T lymphocytes after TCR/CD3 engagement . Therefore, our results indicate that arming with B7‐H3Bi‐Ab triggers ATC activation and tumor cell killing.…”

645. Mucosal-Associated Invariant T cells in Renal Tissue From Patients With Recurrent Urinary Tract Infections

“…Furthermore, the percentage of CD8 + and DN MAIT cells expressing molecules associated with T‐cell activation, such as CD69, 41 and the coinhibitory receptor programmed cell death protein 1 42 was generally low and similar between the immunocompetent adults and the RTR groups (Figures 2A and S6). In addition, the number of CD8 + and DN MAIT cells expressing Ki‐67, a marker of actively cycling cells, appeared to be low and similar between the immunocompetent participants with and without RUTIs (Figure 2A).…”