CD5-mediated inhibition of TCR signaling during intrathymic selection and development does not require the CD5 extracellular domain

Bhandoola, Avinash; Bosselut, Rémy; Yu, Qing; Cowan, Michelle L.; Feigenbaum, Lionel; Love, Paul E.; Singer, Alfred

doi:10.1002/1521-4141(200206)32:6<1811::aid-immu1811>3.0.co;2-g

Cited by 38 publications

(30 citation statements)

References 32 publications

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“…Negative regulatory effects of CD5 are mediated by the cytoplasmic region and can be observed in the absence of the extracellular region of CD5 [24]. Correlation of CD6 expression on thymocytes with resistance to apoptosis [13] is consistent with a negative regulatory role for the CD6 cytoplasmic tail.…”

Section: Introductionmentioning

confidence: 59%

Frontline: Optimal T cell activation requires the engagement of CD6 and CD166

2004

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The T cell surface glycoprotein, CD6 binds CD166 in the first example of an interaction between a scavenger receptor cysteine-rich domain and an immunoglobulin-like domain. We report that in human these proteins interact with a K D =0.4-1.0 ? M and K off n 0.4-0.63 s -1 , typical of many leukocyte membrane protein interactions. CD166 also interacts in a homophilic manner but with around 100-fold lower affinity (K D =29-48 ? M and K off n 5.3 s -1 ). At concentrations, that will block the CD6/CD166 interaction, soluble monomeric CD6 and CD166 inhibit antigen-specific human T cell responses. This is consistent with extracellular engagement between CD6 and CD166 being required for an optimal immune response.

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Section: Introductionmentioning

confidence: 59%

Frontline: Optimal T cell activation requires the engagement of CD6 and CD166

2004

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“…It is further up-regulated in response to TCR engagement during positive͞negative selection at the DP stage. These changes in surface CD5 expression reflect the functional roles demonstrated for CD5, which participates in the fine tuning of the TCR repertoire by negatively regulating TCR signaling during thymocyte development and similarly participates in regulating TCR in mature lymphocytes (5)(6)(7)(8). Thus, the regulatory mechanisms that control CD5 expression are key to lymphocyte development and function.…”

mentioning

confidence: 75%

The E47 transcription factor negatively regulates CD5 expression during thymocyte development

Yang

Contag

Felsher

et al. 2004

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

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The expression of CD5 increases progressively as thymocytes mature. We have shown that CD5 expression is controlled by a tissue-specific regulatory promoter located upstream of the CD5 translation start sites. Deletion of this regulatory promoter, which contains three potential transcription factor binding sites (CCAAT, E2, and ets) reduces the promoter activity to basal level. Of these sites, only ets proved essential for CD5 expression in T cell lines. Here, we introduce a role for the E47 transcription factor and the CD5 promoter E2 site in regulating CD5 expression during thymocyte development. Using T cell lines, we show that (i) mutation of the E2 site in the CD5 regulatory promoter results in a significant elevation of CD5 promoter activity; (ii) the E47 transcription factor binds to the E2 site; and (iii) overexpression of E47 inhibits CD5 expression. We then show, in high-dimensional fluorescence-activated cell sorting studies with primary thymocytes at successive developmental stages, that (i) intracellular E47 levels decrease as surface CD5 expression increases; (ii) E47 expression is down-regulated and CD5 expression is correspondingly upregulated in DN3 thymocytes in RAG-2-deficient mice injected with anti-CD3 to mimic pre-T cell receptor stimulation; and (iii) E47 expression is down-regulated and CD5 expression is up-regulated when double positive thymocytes are stimulated in vitro with anti-CD3. Based on these data, we propose that E47 negatively regulates CD5 expression by interacting with the E2 site in the CD5 regulatory promoter and that decreases in E47 in response to developmental signals are critical to the progressive increase in CD5 expression as thymocytes mature.C D5 (Ly-1) encodes a 67-kDa transmembrane glycoprotein and is expressed at a characteristic level on developmentally and functionally distinct lymphocyte populations both in human and mouse. CD5 is expressed at relatively high levels on all T lineage cells, at low levels on B-1a cells, and is below detectable levels on B-2 cells (1-3). Importantly for studies presented here, CD5 is expressed on thymocytes and increases progressively as thymocytes mature from the double negative (DN) to the double positive (DP) stage and beyond (4).In the thymus, CD5 expression has been shown to be upregulated in response to pre-T cell receptor (TCR) engagement during ␤ selection at the DN stage. It is further up-regulated in response to TCR engagement during positive͞negative selection at the DP stage. These changes in surface CD5 expression reflect the functional roles demonstrated for CD5, which participates in the fine tuning of the TCR repertoire by negatively regulating TCR signaling during thymocyte development and similarly participates in regulating TCR in mature lymphocytes (5-8). Thus, the regulatory mechanisms that control CD5 expression are key to lymphocyte development and function.In studies comparing surface CD5 expression levels with CD5 mRNA levels, we have shown that surface CD5 correlates very closely with CD5 mRNA across a 3...

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“…In certain models of tolerance induction increased CD5 expression has been shown to be critical for T cell anergy (28). Also CD5 expression is modified by the affinity of the antigen -T cell receptor interaction leading to a model of "sensory adaptation" in which low responsiveness of T cells is associated with high CD5 density (38,39). If CD5 also affects TCR signaling in T reg cells in a similar manner, one would predict an increased effectiveness of T reg cells in the absence of CD5, which was brought out well by the studies presented here.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2008

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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.

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CD5-mediated inhibition of TCR signaling during intrathymic selection and development does not require the CD5 extracellular domain

Cited by 38 publications

References 32 publications

Frontline: Optimal T cell activation requires the engagement of CD6 and CD166

Frontline: Optimal T cell activation requires the engagement of CD6 and CD166

The E47 transcription factor negatively regulates CD5 expression during thymocyte development

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

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