CD5 plays an inhibitory role in the suppressive function of murine CD4+ CD25+ Treg cells

Abstract

A subset of CD4 + T cells, the CD4 + CD25 + T reg cells in the lymphoid organs and peripheral blood are known to possess suppressive function. Previous in vitro and in vivo studies have indicated that T cell receptor (TCR) signal is required for development of such 'natural regulatory (T reg ) cells' and for activation of the effector function of CD4 + CD25 + regulatory T cells. CD5 is a cell surface molecule present on all T cells and a subtype of B lymphocytes, the B-1 cells, primarily localized to coelomic cavities, Peyer's patches, tonsils and spleen. CD5 acts as a negative regulator of T cell and B cell signaling via recruitment of SHP-1. Here, we demonstrate that T reg cells obtained from CD5 −/− mice are more potent than those from wild type mice in suppressing the in vitro cell proliferation of anti-CD3 stimulated CD4 + CD25 − responder T cells. This phenomenon was cell contact and GITR dependent. Lack of CD5 expression on T reg cells (from spleen, lymph node and thymus) did not affect the intracellular levels of Foxp3. However, CD5 −/− T reg thymocytes were able to elicit a higher Ca 2+ response to TCR + co-stimulatory signals than the wild type cells. CD5 −/− mice expressed more Foxp3 mRNA in the colon than wild type mice, and additionally, the severity of the DSS-induced colitis in CD5 −/− mice was less than the wild type strain. We suggest that manipulation of CD5 expression or the downstream signaling components of CD4 + CD25 + T reg cells as a potential strategy for therapeutic intervention in cases of auto-immune disorders.

Increased numbers of thymic and peripheral CD4+ CD25+Foxp3+ cells in the absence of CD5 signaling

“…This hyperproliferation was already reported [74] and argues in favor of a role of CD5 as a negative regulator of TCR signaling in mature T cells. Our results showed efficient suppressive activity of CD5 À/À Treg; however, a more detailed study recently showed that Treg obtained from CD5 À/À mice are even more potent than WT Treg in suppressing the in vitro cell proliferation of anti-CD3 stimulated CD4 1 CD25 À responder T cells [75].…”

“…This hyperproliferation was already reported [74] and argues in favor of a role of CD5 as a negative regulator of TCR signaling in mature T cells. Our results showed efficient suppressive activity of CD5 À/À Treg; however, a more detailed study recently showed that Treg obtained from CD5 À/À mice are even more potent than WT Treg in suppressing the in vitro cell proliferation of anti-CD3 stimulated CD4 1 CD25 À responder T cells [75].In conclusion, our data demonstrate that the enrichment of nTreg observed in the absence of CD5 signaling, under conditions of enhanced TCR-mediated signaling is due both to increased nTreg selection and to preferential cell death of naïve thymocytes, while nTreg appear to be less sensitive to conditions of high avidity. The reduced Akt phosphorylation observed CD4 1 CD25 À naïve CD5 À/À thymocytes in response to TCR crosslinking might explain the increased cell death of these cells, suggesting a new potential mechanism for CD5-mediated thymocyte survival.…”

Functional analysis of Foxp3 and CTLA-4 expressing HTLV-1-infected cells in a rat model

“…Sakaguchi et al demonstrated that depletion of the CD5 high T cell population also depleted majority of CD4 + CD25 + T cells simultaneously [27]. Recently, the inhibitory role of CD5 has been reported in the murine T reg cell suppressive function [28]. In our data, CD5 expression was significantly correlated with Foxp3 expression in HTLV-1-infected cells (Fig.…”

Imbalanced signal transduction in regulatory T cells expressing the transcription factor FoxP3

“…33). The amount of CD5 displayed on the cell surface is proportional to the intensity of signals received through the TCR, and CD5 is robustly expressed on Treg cells (34,35). To test whether CD5 more specifically inhibits signaling in Treg cells, we analyzed Erk phosphorylation after CD3/CD28 cross-linking across five matched ranges of surface CD5 (Fig.…”