Cd69 controls inflammation in transplant rejection and cardiovascular diseases

Resumen

The early lymphocyte activation antigen CD69 is a transmembrane protein that is induced early after activation of all bone marrow-derived cells except erythrocytes. It has been described as an anti-inflammatory molecule that negatively regulates inflammation. CD69 deficient mice display enhanced Th17 differentiation and defective Treg cell function presenting an exacerbated form of chronic inflammatory diseases like arthritis, colitis, allergic asthma, contact dermatitis or autoimmune myocarditis due to their inability to resolve inflammation or to maintain immune tolerance. Previous works have shown that Cd69-/- mice are resistant to tumor growth and vaccinia virus infection in part due to NK cells activity. However, the specific contribution of these cells and the mechanism by which CD69 could be regulating their function has not been elucidated. The activation of NK cells depends on the balance between activating/inhibitory signals. Thus, in this work we take advantage of the new Mass Cytometry (CyTOF) technology to perform an unbiased multiparametric phenotyping of Cd69-/- NK cells. By using different animal models such as anti-viral and anti-tumor immunity and graft vs host disease, we have studied the in vivo consequences of Cd69-/- NK cells phenotype. Our study revealed that Cd69-/- NK cells repertoire of inhibitory/activating receptors is altered, exhibiting high levels of non-self and missing self recognition receptors, due to modulation of NKG2D activity. Cd69-/- NK cells are then more efficient in the killing of allogenic and tumor cells, being Cd69-/- mice resistant to aGvHD. All these effects can be reproduced by an anti-CD69 mAb treatment, suggesting that it may be employed in the clinics to reduce GvH effects while potentially maintaining GvL effects. One of the main objectives of this work has been to analyze the role of CD69 expression in lymphocytes in atherosclerosis development. Using chimeric ldlr−/− mice subjected an HFD as atherosclerosis model, we show that the specific deletion of CD69 on the lymphoid compartment leads to an altered Th17/Treg equilibrium and a consequent increase in atheroma plaque size during HFD. Finally, it is well known that gut microbiota shapes local and systemic inflammation. Certain bacteria like SFB induce the accumulation of Th17 cells that might migrate to the periphery affecting systemic immunity. Indeed, several autoimmune disorders, such as multiple sclerosis, EAE, arthritis, type I diabetes or pancreatitis, have been associated with the gut microbiota composition. In this study we have seen that myocarditis induction and progression depends on the microbiota, as in germ free conditions both CD69 proficient and deficient mice preserve heart function and do not present leukocyte infiltration in the heart after EAM induction. Last, CD69 regulates Th17 responses and microbiota composition.