Relevance of CD6-Mediated Interactions in the Regulation of Peripheral T-Cell Responses and Tolerance

Abstract

The CD6 lymphocyte receptor has been involved in the pathophysiology of different autoimmune disorders and is now considered a feasible target for their treatment. In vitro data show the relevance of CD6 in the stabilization of adhesive contacts between T-cell and antigen-presenting cells, and the modulation of T-cell receptor signals. However, the in vivo consequences of such a function are yet undisclosed due to the lack of suitable genetically modified animal models. Here, the in vitro and in vivo challenge of CD6-deficient (CD6−/−) cells with allogeneic cells was used as an approach to explore the role of CD6 in immune responses under relative physiological stimulatory conditions. Mixed lymphocyte reaction (MLR) assays showed lower proliferative responses of splenocytes from CD6−/− mice together with higher induction of regulatory T cells (Treg, CD4+CD25+FoxP3+) with low suppressive activity on T and B-cell proliferation. In line with these results, CD6−/− mice undergoing a lupus-like disorder induced by chronic graft-versus-host disease (cGvHD) showed higher serum titers of anti-double-stranded DNA and nucleosome autoantibodies. This occurred together with reduced splenomegaly, which was associated with lower in vivo bromodesoxyuridine incorporation of spleen cells and with increased percentages of spleen follicular B cells (B2, CD21+CD23hi) and Treg cells. Interestingly, functional analysis of in vivo-generated CD6−/− Treg cells exhibited defective suppressive activity. In conclusion, the data from MLR and cGvHD-induced lupus-like models in CD6−/− mice illustrate the relevance of CD6 in T (and B) cell proliferative responses and, even more importantly, Treg induction and suppressive function in the in vivo maintenance of peripheral tolerance.

Modulation of CD4 T cell function via CD6-targeting

“…However, contact-independent strong stimulation with anti-CD3/CD28 was not affected with addition of anti-CD6. Our observations are in line with a recent report that showed the absence of difference for in vitro Treg induction, between CD6 −/− and CD6 +/+ T cells, when under contact-independent and supra-physiological conventional conditions [39]. It was previously reported that Treg cells from CD6-deficient mice have reduced suppressive function [39].…”

Proteomics and metabolomics identify molecular mechanisms of aging potentially predisposing for chronic lymphocytic leukemia

“…2E-2H). T cell differentiation antigen CD6 and PTGES2 potentially conferring positive cell survival signals (72,73) were found up-regulated, whereas the down-regulation of TLR8 and FCGR1A may reduce immunogenicity (74,75). The mitochondrial stress management and DNA repair proteins (Figs.…”

CD6 deficiency impairs early immune response to bacterial sepsis

“…In case of the major B cell subset not constitutively expressing CD6 (B2), overactivation could result from other indirect causes such as a defective function of cells with regulatory/suppressive activity. Indeed, previous work from our group shows that steady state Cd6 −/− mice already present higher frequencies of regulatory T (Treg) cells with decreased suppressive activity ( Consuegra-Fernández et al., 2017 ; Orta-Mascaró et al., 2016 ). Ex vivo cell analyses showed that spleens from Cd6 −/− mice post-CLP-induced sepsis also undergo higher Treg cell induction, associated to lower induction of CD69 surface expression, a maker correlating with Treg suppressive function ( Yu et al., 2018 ) ( Figure S2 ).…”