Identification of functionally relevant phoshorylatable serine clusters in the cytoplasmic region of the human CD6 lymphocyte surface receptor

Bonet, Lizette; Farnós, Montserrat; Martínez-Florensa, Mario; Martínez, Vanesa G.; Lozano, Francisco

doi:10.1016/j.febslet.2013.05.043

Cited by 16 publications

(14 citation statements)

References 30 publications

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“…Mitogen-activated PBL is known to express no less than five different alternatively spliced CD6 cytoplamic isoforms involving loss of structural motifs relevant to signal-transducing function (42, 43). Likewise, the extracellular isoform (CD6Δ3) lacking the CD166/ALCAM-binding domain (D3) of CD6—and consequently unable to localize at the APC–T-cell interface during IS formation—is upregulated and dominates upon T-cell activation (33).…”

Section: Discussionmentioning

confidence: 99%

“…Thus, T-cell activation could contribute to reduced CD6 surface levels by both proteolytic events and Cbl-mediated ubiquitination, which could be direct or indirect through its physical association with CD5. Regarding the putative contribution of alternative splicing to membrane-bound CD6 down-modulation, available reports by independent groups (33, 42, 43) have not identified alternatively spliced mRNAs coding for sCD6 and/or CD6 isoforms devoid of its entire extracellular region.…”

Section: Discussionmentioning

confidence: 99%

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Human CD6 Down-Modulation following T-Cell Activation Compromises Lymphocyte Survival and Proliferative Responses

et al. 2017

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Available evidence indicates that the CD6 lymphocyte surface receptor is involved in T-cell developmental and activation processes, by facilitating cell-to-cell adhesive contacts with antigen-presenting cells and likely modulating T-cell receptor (TCR) signaling. Here, we show that in vitro activation of human T cells under different TCR-ligation conditions leads to surface downregulation of CD6 expression. This phenomenon was (i) concomitant to increased levels of soluble CD6 (sCD6) in culture supernatants, (ii) partially reverted by protease inhibitors, (iii) not associated to CD6 mRNA down-regulation, and (iv) reversible by stimulus removal. CD6 down-modulation inversely correlated with the upregulation of CD25 in both FoxP3− (Tact) and FoxP3+ (Treg) T-cell subsets. Furthermore, ex vivo analysis of peripheral CD4+ and CD8+ T cells with activated (CD25+) or effector memory (effector memory T cell, CD45RA−CCR7−) phenotype present lower CD6 levels than their naïve or central memory (central memory T cell, CD45RA−CCR7+) counterparts. CD6lo/− T cells resulting from in vitro T-cell activation show higher apoptosis and lower proliferation levels than CD6hi T cells, supporting the relevance of CD6 in the induction of proper T-cell proliferative responses and resistance to apoptosis. Accordingly, CD6 transfectants also showed higher viability when exposed to TCR-independent apoptosis-inducing conditions in comparison with untransfected cells. Taken together, these results provide insight into the origin of sCD6 and the previously reported circulating CD6-negative T-cell subset in humans, as well as into the functional consequences of CD6 down-modulation on ongoing T-cell responses, which includes sensitization to apoptotic events and attenuation of T-cell proliferative responses.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Human CD6 Down-Modulation following T-Cell Activation Compromises Lymphocyte Survival and Proliferative Responses

et al. 2017

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“…Costimulation by CD6 depends on ligand binding at the cell surface and an interaction between the phosphorylated C-terminal tyrosine Y662 and the adaptor protein SH2 domain-containing leukocyte molecule of 76 kDa (SLP-76) (1, 4, 8, 9). The interaction between CD6 and SLP-76 is clearly important for costimulation by CD6, but there are data to indicate that other regions of the extensive cytoplasmic region regulate its function through serine and tyrosine phosphorylation (10–12). …”

Section: Introductionmentioning

confidence: 99%

T Cell Costimulation by CD6 Is Dependent on Bivalent Binding of a GADS/SLP-76 Complex

Breuning

Brown

2017

Molecular and Cellular Biology

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The cell surface receptor CD6 regulates T cell activation in both activating and inhibitory manners. The adaptor protein SLP-76 is recruited to the phosphorylated CD6 cytoplasmic Y662 residue during T cell activation, providing an activating signal to T cells. In this study, a biochemical approach identified the SH2 domain-containing adaptor protein GADS as the dominant interaction partner for the CD6 cytoplasmic Y629 residue. Functional experiments in human Jurkat and primary T cells showed that both mutations Y629F and Y662F abolished costimulation by CD6. In addition, a restraint on T cell activation by CD6 was revealed in primary T cells expressing CD6 mutated at Y629 and Y662. These data are consistent with a model in which bivalent recruitment of a GADS/SLP-76 complex is required for costimulation by CD6.

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“…CD6 has a cytoplasmic tail devoid of intrinsic catalytic activity, but includes consensus motifs for Tyr (9) and Thr/Ser (22, 23) phosporylation and interaction with different intracellular signaling effectors such as mitogen-activated protein kinases (24), SH2 domain-containing leukocyte protein of 76 kDa (SLP-76) (21, 25) and syntenin (26). This allows CD6 modulating the activation responses triggered through the T-cell receptor (TCR)/CD3 complex to which it is physically associated at the center of the IS (14, 15).…”

Section: Introductionmentioning

confidence: 99%

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

Consuegra-Fernández¹,

Martínez-Florensa²,

Aranda³

et al. 2017

Front. Immunol.

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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.

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Identification of functionally relevant phoshorylatable serine clusters in the cytoplasmic region of the human CD6 lymphocyte surface receptor

Cited by 16 publications

References 30 publications

Human CD6 Down-Modulation following T-Cell Activation Compromises Lymphocyte Survival and Proliferative Responses

Human CD6 Down-Modulation following T-Cell Activation Compromises Lymphocyte Survival and Proliferative Responses

T Cell Costimulation by CD6 Is Dependent on Bivalent Binding of a GADS/SLP-76 Complex

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

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