Is CD69 an effective brake to control inflammatory diseases?

Abstract

Early studies described CD69 as a leukocyte activation marker, and suggested its involvement in the activation of different leukocyte subsets as well as in the pathogenesis of chronic inflammation. However, recent investigations have showed that CD69 knockout mice exhibit an enhanced susceptibility to different inflammatory diseases, mainly those mediated by Th17 lymphocytes. The recent discovery of a ligand for CD69 expressed on Dendritic cells, Galectin-1, has confirmed the immunoregulatory role of CD69 mainly by the inhibition of Th17 differentiation and function in mice and humans. In this regard, the expression of CD69, both in Th17 lymphocytes and by a subset of regulatory T cells, has an important role in the control of the immune response and the inflammatory phenomenon. Therefore, different evidences indicate that CD69 exerts a complex immuno-regulatory role in humans, and that it could be considered as target molecule for the therapy of immune-mediated diseases. Keywords CD69; Inflammatory diseases; Treg lymphocytes; Th17 lymphocytes, Immuno-regulation CD69 IS AN EARLY ACTIVATION ANTIGEN OF IMMUNE CELLSCD69 is a type II C-lectin membrane receptor with a scarce expression in resting lymphocytes that is rapidly induced upon cell activation. CD69 gene maps at human chromosome 12, and behaves as an early activation gene that contains responsive elements for the transcription factors NF-κB, ERG-1 and AP-1 (Fig. 1A). Early in vitro data as well as the prominent expression of CD69 in chronic inflammatory cell infiltrates suggested that this receptor has an important role in the activation of leukocytes, exerting a proinflammatory effect. Recent studies in CD69-deficient mice indicate that this molecule Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts exerts a complex and interesting role in the modulation of the immune response and the inflammatory phenomenon [1]. However, these studies have been controversial for a while since two different models of CD69 deficient mice have been described with opposite effects in the development of T-cell independent arthritis and Th2-dependent asthma. Murata et al. 2003 [2] described a CD69 knockout mice that were protected towards arthritis induced by anti-type II collagen antibodies whereas Lamana et al. 2006 [3] revisited the same disease model with an independent CD69-deficient mice and found that the lack of CD69 did not inhibits joint inflammation. Lamana et al. used monoclonal antibodies against CD69 in wild type mice, that downregulates the expression of the molecule in the membrane, to bypass putative different genetic alterations in the process of generation of these two different animal models. These investigations confirmed that the lack of CD69 do not protects the mice towards the T-independent model of neutrophil-mediated arthritis.Regarding the role of CD69 in asthma, Miki-Hosokawa et al. 2009 described that the reduced migration of Th2 cells accounts for the inhibition of lung inflammation in a model of CD69 null mice [4]...

Regulatory and activated effector T cells in chronic hepatitis C virus: Relation to autoimmunity

“…This means that T effector cells dominate over T regulatory cells favoring autoimmunity and initiating pathological immune response with production of autoantibodies. Similar findings were reported by González-Amaro et al[37]. …”

Early pediatric atopic dermatitis shows only a cutaneous lymphocyte antigen (CLA)+ TH2/TH1 cell imbalance, whereas adults acquire CLA+ TH22/TC22 cell subsets

“…CD69 also functions as an immunoregulatory receptor, 62 and has been reported to have opposing functional roles in inflammatory responses. 62 In AD, its expression on eosinophils was associated with high IgE levels and active inflammation, 63 and data from other allergic diseases indicate that CD69 promotes the inflammatory process.…”

“…62 In AD, its expression on eosinophils was associated with high IgE levels and active inflammation, 63 and data from other allergic diseases indicate that CD69 promotes the inflammatory process. 64 Our data show that CD69 is the only activation marker higher in children vs. adults with AD.…”

Thymus-Derived Regulatory T Cell Development Is Regulated by C-Type Lectin-Mediated BIC/MicroRNA 155 Expression

“…Using a combined genetic model of Foxp3 reporter and cd69 knockout mice and genetic inhibition approaches, we unequivocally demonstrate that the activation of the CD69 pathway promotes STAT5 phosphorylation, BIC/miR-155 expression, and SOCS-1 inhibition. The role of CD69 as a negative regulator of the immune system has remained a controversial issue during the last years (23). However, very recent studies by independent groups show that CD69 plays a crucial role in the suppressor function of mouse and human Treg cells as well as in the generation of in vitro-induced Treg cells (12,16,(24)(25)(26).…”