Fine Tuning of TCR Signaling by CD5

Abstract

Current data indicate that CD5 functions as an inhibitor of TCR signal transduction. Consistent with this role, thymocyte selection in TCR transgenic/CD5−/− mice is altered in a manner suggestive of enhanced TCR signaling. However, the impact of CD5 deletion on thymocyte selection varies depending on the transgenic TCR analyzed, ranging from a slight to a marked shift from positive toward negative selection. An explanation for the variable effect of CD5 on selection is suggested by the observation that CD5 surface expression is regulated by TCR signal intensity during development and CD5 surface levels on mature thymocytes and T cells parallel the avidity of the positively selecting TCR/MHC/ligand interaction. In this study, we generated mice that overexpress CD5 during thymocyte development (CD5-tg), and then examined the effect of CD5 overexpression or CD5 deletion (CD5−/−) on selection of thymocytes that express the same TCR transgenes. The results demonstrate that the effect on thymocyte selection of altering CD5 expression depends on the avidity of the selecting interaction and, consequently, the level of basal (endogenous) CD5 surface expression. Substitution of endogenous CD5 with a transgene encoding a truncated form of the protein failed to rescue the CD5−/− phenotype, demonstrating that the cytoplasmic domain of CD5 is required for its inhibitory function. Together, these results indicate that inducible regulation of CD5 surface expression during thymocyte selection functions to fine tune the TCR signaling response.

GATA3 controls the expression of CD5 and the T cell receptor during CD4 T cell lineage development

“…By analysis of CD2-GATA3 transgenic and Gata3 conditional knockout mouse models, as well as CD2-GATA3 transgenic mice that were crossed into various TCR-transgenic mice, we show in this report that GATA3 modulates the surface expression level of the glycoprotein CD5 and enhances TCR expression during CD4 T lineage development in vivo. The regulatory mechanisms that control CD5 expression are key to lymphocyte development and function, because CD5 is a negative regulator of TCR signaling during thymocyte development and therefore participates in the finetuning of the TCR repertoire [13][14][15][16]. Interestingly, because GATA3 is induced by TCR signaling [7], our finding that GATA3 controls TCR up-regulation and CD5 down-regulation implicates GATA3 in a positive feedback loop that increases TCR surface expression during CD4 T lineage development.…”

“…As targeted deletion of CD5 has been shown to reduce DP cellularity in various TCR-transgenic models, including HY and DO11.10 [16,31], it is likely that the reduction of DP cell numbers in the CD2-GATA3 transgenic models is a result of decreased CD5 expression. As CD5 acts as a negative regulator of TCR-mediated signal transduction [13,16], reduction of CD5 expression levels in CD2-GATA3-expressing DP cells is expected to increase TCR signal strength, which will result in negative selection and thus deletion.…”

“…As targeted deletion of CD5 has been shown to reduce DP cellularity in various TCR-transgenic models, including HY and DO11.10 [16,31], it is likely that the reduction of DP cell numbers in the CD2-GATA3 transgenic models is a result of decreased CD5 expression. As CD5 acts as a negative regulator of TCR-mediated signal transduction [13,16], reduction of CD5 expression levels in CD2-GATA3-expressing DP cells is expected to increase TCR signal strength, which will result in negative selection and thus deletion. However, it cannot be excluded that the impaired thymocyte expansion and the partial developmental arrest found in thymocytes with premature TCRab expression and signaling [32] may also contribute to the observed reduction in the DP cell population in TCR CD2-GATA3 double-transgenic mice.…”

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

“…Although initial studies on CD5 À/À mice did not reveal major defects in T-cell development [44], further analysis using TCR transgenic mice showed that CD5 can influence the outcome of thymocyte selection depending on the avidity of the TCR-peptide/ MHC interaction. Thus, in the absence of CD5, thymocytes with high affinity TCR were negatively selected, likely due to increased TCRmediated signaling [43,45].Since selection of nTreg appear to require high affinity/avidity interactions [46], we hypothesized that CD5 might be involved in their generation. Here, we describe that the absence of CD5 leads to increased numbers of thymic and peripheral nTreg, accompanied by increased cell death of naïve thymocytes.…”

“…Although initial studies on CD5 À/À mice did not reveal major defects in T-cell development [44], further analysis using TCR transgenic mice showed that CD5 can influence the outcome of thymocyte selection depending on the avidity of the TCR-peptide/ MHC interaction. Thus, in the absence of CD5, thymocytes with high affinity TCR were negatively selected, likely due to increased TCRmediated signaling [43,45].…”