CD69 is an immunoregulatory molecule induced following activation

doi:10.1016/j.it.2004.12.006

Trends in Immunology

Volume 26, Issue 3, March 2005, Pages 136-140

https://doi.org/10.1016/j.it.2004.12.006 Get rights and content

CD69 is an early leukocyte activation molecule expressed at sites of chronic inflammation. The precise role of CD69 in immunity has not been elucidated owing to the absence of a known ligand and adequate in vivo models to study its physiological function. Although previous in vitro studies suggest that CD69 is an activatory molecule in different leukocyte subsets, recent studies in CD69-deficient mice have revealed a non-redundant role for this receptor in downregulation of the immune response through the production of the pleiotropic cytokine transforming growth factor-β (TGF-β). The possible cellular and molecular mechanisms of action of this molecule are discussed herein.

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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Trends in Immunology

CD69 is an immunoregulatory molecule induced following activation

Introduction

Section snippets

Early data: CD69 exerts a co-stimulatory effect in vitro

Recent insights: immunoregulatory role of CD69

Possible regulatory steps affected by CD69

CD69 and regulatory T cells

Concluding remarks

Acknowledgements

Immunol. Today

Cell. Immunol.

Blood

Blood

Immunity

Blood

Trends Immunol.

Molecular characterization of the early activation antigen CD69: a type II membrane glycoprotein related to a family of natural killer cell activation antigens

Eur. J. Immunol.

Molecular cloning, expression, and chromosomal localization of the human earliest lymphocyte activation antigen AIM/CD69, a new member of the C-type animal lectin superfamily of signal-transmitting receptors

J. Exp. Med.

Regulation of immune responses through inhibitory receptors

Annu. Rev. Immunol.

Src-dependent Syk activation controls CD69-mediated signaling and function on human NK cells

J. Immunol.

CD69-triggered ERK activation and functions are negatively regulated by CD94/NKG2-A inhibitory receptor

Eur. J. Immunol.

CD69 in resting and activated T lymphocytes. Its association with a GTP binding protein and biochemical requirements for its expression

J. Immunol.

Regulating T helper cell immunity through antigen responsiveness and calcium entry

Nat. Immunol.

Functional analysis of ligand-binding and signal transduction domains of CD69 and CD23 C-type lectin leukocyte receptors

J. Immunol.

T cell activation via Leu-23 (CD69)

J. Immunol.

Triggering of T cell proliferation through AIM, an activation inducer molecule expressed on activated human lymphocytes

J. Exp. Med.

Tumor necrosis factor-α production induced in T lymphocytes through the AIM/CD69 activation pathway

Eur. J. Immunol.

Triggering of human monocyte activation through CD69, a member of the natural killer cell gene complex family of signal transducing receptors

J. Exp. Med.

CD69 is expressed on platelets and mediates platelet activation and aggregation

J. Exp. Med.

Interleukin-15 mediates T cell-dependent regulation of tumor necrosis factor-α production in rheumatoid arthritis

Nat. Med.

Functional characterization of an antigen involved in an early step of T-cell activation

Proc. Natl. Acad. Sci. U. S. A.

A potential role for CD69 in thymocyte emigration

Int. Immunol.

The generation of mature, single-positive thymocytes in vivo is dysregulated by CD69 blockade or overexpression

J. Immunol.

Upregulated expression and function of VLA-4 fibronectin receptors on human activated T cells in rheumatoid arthritis

J. Clin. Invest.