Trends in Immunology
CD69 is an immunoregulatory molecule induced following activation
Introduction
Self-limitation of the immune response is crucial to its control and molecules induced during lymphocyte activation might act as negative regulators. In this Opinion, we discuss recent results that identify CD69 as a potential negative regulator. CD69 is an early membrane receptor transiently expressed on lymphocyte activation, not detected in resting lymphocytes, and selectively expressed in chronic inflammatory infiltrates and at the sites of active immune responses in vivo. Although early in vitro data suggested that CD69 exerts a proinflammatory function, recent in vivo results indicate that this receptor might act as a regulatory molecule, modulating the inflammatory response. In addition, CD69 might act specifically on an as yet uncharacterized T-cell regulatory subset. These recent insights provide a novel view of the function of this receptor, even though a full picture of the spatial and temporal regulation of the immune response by CD69 will require detailed characterization of its ligand(s).
Section snippets
Early data: CD69 exerts a co-stimulatory effect in vitro
The CD69 gene is located within the natural killer (NK) gene complex on mouse chromosome 6 and human chromosome 12 1, 2 and codes for a type II C-type lectin ascribed to the family of NK receptors. CD69 is expressed following activation in all bone marrow-derived cells except erythrocytes (reviewed in Ref. [3]). Most NK lectin receptors directly mediate their activatory or inhibitory effects through their cytoplasmic domains [4]. However, the cytoplasmic domain of CD69 is short and lacks any
Recent insights: immunoregulatory role of CD69
The in vivo models initially chosen for the study of CD69 function were based on its pattern of expression. Studies in CD69-transgenic mice focused on thymic selection 19, 20, a process in which CD69 expression is transiently induced (Box 1). Despite the in vitro evidence suggesting a possible proinflammatory role for CD69, constitutive expression of CD69 by T cells in transgenic mice is not associated with inflammatory conditions 19, 20. Furthermore, analysis of antigen-specific responses in
Possible regulatory steps affected by CD69
Recent results indicate that CD69 modulates the synthesis of immunoregulatory molecules. Initial T-cell activation and antigen-driven T-cell proliferation are not affected by the absence of CD69 [21]. However, CD69 might affect the immune response during T-cell differentiation (Figure 2), involving immunoregulatory cytokines that include, but might not be limited to, TGF-β, which controls T-cell differentiation [31] and that, depending on the stimulation provided, could also regulate
CD69 and regulatory T cells
T regulatory (Treg) cells have an impaired capacity to respond to proliferative signals and are able to inhibit other immune cell functions through cell–cell contact or through the production of anti-inflammatory cytokines, such as TGF-β, IL-10 or IL-4 39, 40. Natural Treg cells are generated in the thymus and are characterized by their high expression of CD25, which suppresses effector responses through cell–cell contact in a cytokine-independent manner. However, adaptive Treg cells are
Concluding remarks
Previous results in vitro pointed to CD69 as a stimulatory receptor, however, recent results in vivo have shown that the behaviour of CD69 is more complex. The absence of CD69 leads to an enhanced immune response in two independent models: increased severity of a T-cell driven animal arthritis model [25] and augmented rejection of NK-sensitive tumours [27]. CD69 mediates TGF-β production and the effect of this pleiotropic cytokine might account for the regulatory effect of CD69, although other
Acknowledgements
We apologize to many colleagues whose important contributions have not been quoted due to space constraints. We want to thank R. González-Amaro, R. R. Lobb and M. Vicente-Manzanares for helpful discussion. This work was supported by grant BMC02–00563 from the Spanish Ministry of Education and Science, and the Ayuda a la Investigación Básica 2002 from Juan March Foundation. D.S. is supported by BEFI 01/9191 from the Instituto de Salud Carlos III (Ministerio de Sanidad y Consumo).
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