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 or reduced susceptibility to different experimental models of inflammatory diseases, including those mediated by T helper 17 (Th17) lymphocytes. 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 evidence indicates that CD69 exerts a complex immunoregulatory role in humans, and that it could be considered as a target molecule for the therapy of immune-mediated diseases.

Keywords: CD69; Th17 lymphocytes; Treg lymphocytes; immunoregulation; inflammatory diseases.

Fig. 1. Main characteristics of CD69

(A) Gene encoding for CD69 is localized in the natural killer (NK) gene complex. CD69 belongs to a family of receptors that modulate the immune response, the NK gene complex. NK cluster encodes several proteins as CD94 receptors or NKG2 receptor family of proteins. CD69 gene is localized at human chromosome 12 and mouse chromosome 6, and the sequence contains a potential TATA element with a number of putative binding sites for inducible transcription factors (NF-κB, ERG-1, AP-1) involved in the control of CD69 gene expression. (B) CD69 protein structure and interacting proteins. CD69 belongs to the C-type lectin receptors family (CTLD), and its structure is shared by other members as CD94. Three-dimensional analysis of human CD69 structure has revealed that it is expressed as a homodimer, formed by two identical polypeptide chains with different degrees of glycosylation (and molecular weights of 33 and 27 kDa), linked by a disulphide bridge. The cytoplasmic tail of mouse and human CD69 associates with Jak3/Stat5 signaling proteins, which regulates the transcription of RORγt/RORC2 and therefore the differentiation of Th17 lymphocytes.

Fig. 2. Immuno-regulatory role of CD69

Natural T regulatory (nTreg, left) lymphocytes, which do not constitutively express CD69, are able to synthesize this molecule, when are activated in the periphery. Upon its engagement with their putative endogenous ligands (expressed on the surface of immune cells, including antigen presenting cells), the intracellular signals generated through CD69 would enhance the immunosuppressive activity of nTreg cells and would increase the synthesis of TGF-β. Another subset of Treg lymphocytes (CD4⁺ CD25⁻, with a variable expression of Foxp3, middle left) is characterized by the constitutive expression of CD69. Upon activation, these cells become CD25⁺ and, as in the case of nTreg lymphocytes they would increase their immuno-regulatory activity after the engagement of their CD69 molecules. In the case of naïve non-regulatory CD4⁺ and CD8⁺ T cells (middle right, and right, respectively), CD69 behaves as an activation molecule, appearing on the cell surface when these cells are activated by antigen presenting cells or other stimuli. When these cells are differentiated into effector (helper and cytotoxic) lymphocytes, they remain as CD69⁺, and the engagement of this molecule would diminish the pro-inflammatory activity of these cells. However, and as stated in the text, it is also feasible that the expression of CD69 by CD4⁺ or CD8⁺ effector lymphocytes is associated, under certain circumstances, with an enhanced pathogenic capability of these cells Thus, CD69 seems to exert a complex but relevant immuno-regulatory role at different cell levels, affecting the severity of immune-mediated diseases, mainly those characterized by chronic inflammation.