Human CD6 possesses a large, alternatively spliced cytoplasmic domain

Robinson, William H.; Vegvar, Henry E. Neuman de; Prohaska, Susan; Rhee, Joon Whan; Parnes, Jane R.

doi:10.1002/eji.1830251008

Cited by 36 publications

(21 citation statements)

References 27 publications

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“…CD5 and CD6 both contain several tyrosine residues in their cytoplasmic regions, the tail of CD6 being remarkably long (244 amino acids), with nine tyrosine residues (7,33). Initial studies with CD5 and CD6 monoclonal antibodies (mAbs) suggested a positive regulatory role for these proteins in regulating T-cell responses (1,38).…”

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confidence: 99%

CD6 Regulates T-Cell Responses through Activation-Dependent Recruitment of the Positive Regulator SLP-76

Hassan

Simmonds

Clarkson

et al. 2006

Molecular and Cellular Biology

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Deciphering the role of lymphocyte membrane proteins depends on dissecting the role of a protein in the steady state and on engagement with its ligand. We show that expression of CD6 in T cells limits their responsiveness but that engagement by the physiological ligand CD166 gives costimulation. This costimulatory effect of CD6 is mediated through phosphorylation-dependent binding of a specific tyrosine residue, 662Y, in its cytoplasmic region to the adaptor SLP-76. A direct interaction between SLP-76 and CD6 was shown by binding both to a phosphorylated peptide (equilibrium dissociation constant [K D ] ‫؍‬ 0.5 M at 37°C) and, using a novel approach, to native phosphorylated CD6. Evidence that CD6 and SLP-76 interact in cells was obtained in coprecipitation experiments with normal human T cells. Analysis of human CD6 mutants in a murine T-cell hybridoma model showed that both costimulation by CD6 and the interaction between CD6 and SLP-76 were dependent on 662Y. The results have implications for regulation by CD6 and the related T-cell surface protein, CD5.Expression of T-cell surface proteins which are involved in regulating antigen-specific T-cell activation is coordinated by the T-cell receptor (TCR). During positive selection, both TCR and a number of T-cell surface proteins, including CD6, CD5, and CD2, are upregulated and remain expressed on mature T cells (36,40). These proteins regulate antigen-specific responses through cell-cell contact and have substantial cytoplasmic regions which link to intracellular signaling machinery (Fig. 1A). Cell surface ligands for CD2 and CD6 have been identified (Fig. 1A), and there is evidence that CD5 mediates cell-cell contact (reference 11 and references therein). CD6 and CD5 are unusual in that their extracellular regions are comprised of scavenger receptor cysteine-rich domains instead of the more-common immunoglobulin (Ig)-like domains found in other T-cell surface proteins, such as CD2, CD4, CD8, etc. CD6 and CD5 are linked in the genome and have similar structures and expression patterns (3,36,38). CD6 binds the immunoglobulin superfamily protein CD166 (6) (Fig. 1A). CD6 is highly expressed on resting T cells, whereas CD166 is expressed on antigen-presenting cells, consistent with engagement of CD6 by CD166 being necessary for optimal antigen-specific T-cell activation (19). The functional role of another unidentified potential ligand for CD6 has not yet been described (34).CD5 and CD6 both contain several tyrosine residues in their cytoplasmic regions, the tail of CD6 being remarkably long (244 amino acids), with nine tyrosine residues (7, 33). Initial studies with CD5 and CD6 monoclonal antibodies (mAbs) suggested a positive regulatory role for these proteins in regulating T-cell responses (1, 38). However, studies with CD5-deficient mice cast CD5 in the light of a negative regulator. This hypothesis was based on increased sensitivity to activation of cells deficient in CD5 (39). Negative effects were shown to be mediated by the cytoplasmic region (4, 30) and in...

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CD6 Regulates T-Cell Responses through Activation-Dependent Recruitment of the Positive Regulator SLP-76

Hassan

Simmonds

Clarkson

et al. 2006

Molecular and Cellular Biology

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“…In fact, CD6 expression correlates with thymocyte-positive selection and resistance to apoptosis (15). CD6 possesses a long cytoplasmic domain well suited for signal transduction (23), but the intracellular consequences of CD6 engagement by its ligand are mostly unknown. It has been shown, however, that TCR/CD3 stimulation induces tyrosine phosphorylation of CD6 (11,12), which might then promote recruitment of signaling molecules and contribute to building the IS.…”

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confidence: 99%

Relevance of CD6-Mediated Interactions in T Cell Activation and Proliferation

Gimferrer¹,

Calvo

Mittelbrunn

et al. 2004

The Journal of Immunology

132

152

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CD6 is a cell surface receptor expressed on immature thymocytes and mature T and B1a lymphocytes. The ultimate function of CD6 has not been deciphered yet, but much evidence supports a role for CD6 in T cell activation and differentiation. In this study, we show that a fraction of CD6 molecules physically associates with the TCR/CD3 complex by coimmunoprecipitation, cocapping, and fluorescence resonance energy transfer experiments. Image analysis of Ag-specific T-APC conjugates demonstrated that CD6 and its ligand, activated leukocyte cell adhesion molecule (CD166), colocalize with TCR/CD3 at the center of the immunological synapse, the so-called central supramolecular activation cluster. The addition of a soluble rCD6 form significantly reduced the number of mature Ag-specific T-APC conjugates, indicating that CD6 mediates early cell-cell interactions needed for immunological synapse maturation to proceed. This was in agreement with the dose-dependent inhibition of CD3-mediated T cell proliferation induced by soluble rCD6. Taken together, our data illustrate the important role played by the intra- and intercellular molecular interactions mediated by CD6 during T cell activation and proliferation processes.

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“…The cytoplasmic domain of CD6 is unusually long and also contains two well-conserved proline-rich sequences, which are potential binding sites for SH3 domain-containing proteins well suited for signal transduction (16,18). Indeed, the rat homolog of CD6 has been shown to associate with protein tyrosine kinases of different families, namely Src-family kinases Lck and Fyn, Zap70 of the Syk family, and the Tec-family kinase Itk (19).…”

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Extracellular Isoforms of CD6 Generated by Alternative Splicing Regulate Targeting of CD6 to the Immunological Synapse

Castro

Oliveira

Nunes

et al. 2007

The Journal of Immunology

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The great majority of mammalian genes yield multiple transcripts arising from differential mRNA processing, but in very few instances have alternative forms been assigned distinct functional properties. We have cloned and characterized a new isoform of the accessory molecule CD6 that lacks the CD166 binding domain and is expressed in rat and human primary cells. The novel isoform, CD6Δd3, results from exon 5 skipping and consequently lacks the third scavenger receptor cysteine-rich (SRCR) domain of CD6. Differential expression of the SRCR domain 3 resulted in a remarkable functional difference: whereas full-length CD6 targeted to the immunological synapse, CD6Δd3 was unable to localize at the T cell:APC interface during Ag presentation. Analysis of expression of CD6 variants showed that, while being more frequent in coexpression with full-length CD6, the CD6Δd3 isoform constituted the sole species in a small percentage of T cells. In the rat thymus, CD6Δd3 is less represented in double-positive thymocytes but is detectable in nearly 50% of single-positive CD4 or CD8 thymocytes, suggesting that CD6 switching between full-length and Δd3 isoforms may be involved in thymic selection. Strikingly, CD6Δd3 is markedly up-regulated upon activation of T lymphocytes, partially substituting full-length CD6, as evaluated by RT-PCR analysis at the single-cell level, by immunoblotting, and by flow cytometry using Abs recognizing SRCR domains 1 and 3 of human CD6. This elegant mechanism controlling the expression of the CD166 binding domain may help regulate signaling delivered by CD6, through different types of extracellular engagement.

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Human CD6 possesses a large, alternatively spliced cytoplasmic domain

Cited by 36 publications

References 27 publications

CD6 Regulates T-Cell Responses through Activation-Dependent Recruitment of the Positive Regulator SLP-76

CD6 Regulates T-Cell Responses through Activation-Dependent Recruitment of the Positive Regulator SLP-76

Relevance of CD6-Mediated Interactions in T Cell Activation and Proliferation

Extracellular Isoforms of CD6 Generated by Alternative Splicing Regulate Targeting of CD6 to the Immunological Synapse

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