CD5 Signal Transduction: Positive or Negative Modulation of Antigen Receptor Signaling

Lozano, Francisco; Simarro, Marı́a; Calvo, Javier; Vila, Josep M.; Padilla, Olga; Bowen, Michael A.; Campbell, Kerry S.

doi:10.1615/critrevimmunol.v20.i4.30

Cited by 60 publications

(59 citation statements)

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“…They exhibit important differences in their cytoplasmic regions, but their extracellular regions are exclusively composed of three consecutive SRCR domains, which show extensive amino acid sequence identity (1,10). Functionally, they are physically associated to the antigenspecific receptor complex present on T (TCR/CD3) and B (BCR) cells, where they contribute to either positive or negative modulation of the activation and differentiation signals delivered by that receptor complex (2,11,12). In the present study we have explored the bacterial binding capabilities of the ectodomains of the human lymphocyte receptors CD5 and CD6, both known to exist as membrane receptors, but also as soluble receptors circulating in serum (13,14).…”

Section: T He Scavenger Receptor Cysteine-rich Superfamily (Srcr-sf)mentioning

confidence: 99%

CD6 binds to pathogen-associated molecular patterns and protects from LPS-induced septic shock

Sarrias

Farnós

Mota

et al. 2007

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

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102

118

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CD6 is a lymphocyte receptor that belongs to the scavenger receptor cysteine-rich superfamily. Because some members of the scavenger receptor cysteine-rich superfamily act as pattern recognition receptors for microbial components, we studied whether CD6 shares this function. We produced a recombinant form of the ectodomain of CD6 (rsCD6), which was indistinguishable (in apparent molecular mass, antibody reactivity, and cell binding properties) from a circulating form of CD6 affinity-purified from human serum. rsCD6 bound to and aggregated several Gram-positive and -negative bacterial strains through the recognition of lipoteichoic acid and LPS, respectively. The K d of the LPS-rsCD6 interaction was 2.69 ؎ 0.32 ؋ 10 ؊8 M, which is similar to that reported for the LPS-CD14 interaction. Further experiments showed that membrane CD6 also retains the LPS-binding ability, and it results in activation of the MAPK signaling cascade. In vivo experiments demonstrated that i.p. administration of rsCD6 before lethal LPS challenge significantly improved mice survival, and this was concomitant with reduced serum levels of the proinflammatory cytokines TNF-␣, IL6, and IL-1␤. In conclusion, our results illustrate the unprecedented bacterial binding properties of rsCD6 and support its therapeutic potential for the intervention of septic shock syndrome or other inflammatory diseases of infectious origin.bacterial cell component ͉ innate immunity ͉ lymphocyte surface receptor

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Section: T He Scavenger Receptor Cysteine-rich Superfamily (Srcr-sf)mentioning

confidence: 99%

CD6 binds to pathogen-associated molecular patterns and protects from LPS-induced septic shock

Sarrias

Farnós

Mota

et al. 2007

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

Self Cite

102

118

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“…However, the 5 immunophenotypic features of T cells in other subtypes of HLH have not been fully characterized. Human CD5 is a membrane glycoprotein that belongs to the scavenger receptor cysteine-rich family of receptors [6][7][8][9]. It is expressed on thymocytes, mature peripheral T cells and a small population of B cells, and is involved in the modulation of antigen-specific receptor-mediated activation and differentiation signals [6][7][8][9].…”

Section: Introductionmentioning

confidence: 99%

“…Human CD5 is a membrane glycoprotein that belongs to the scavenger receptor cysteine-rich family of receptors [6][7][8][9]. It is expressed on thymocytes, mature peripheral T cells and a small population of B cells, and is involved in the modulation of antigen-specific receptor-mediated activation and differentiation signals [6][7][8][9]. It has recently been reported that CD5 is recruited and colocalized with CD3 at the immunological synapse and inhibits T-cell receptor (TCR) signaling in T cells without interfering with immunological synapse formation [10].…”

Section: Introductionmentioning

confidence: 99%

Down-regulation of CD5 expression on activated CD8+ T cells in familial hemophagocytic lymphohistiocytosis with perforin gene mutations

et al. 2013

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Hemophagocytic lymphohistiocytosis (HLH) is characterized by uncontrolled activation of T cells and macrophages with overproduction of cytokines. Familial HLH type2 (FHL2) is the most common form of primary HLH and is caused by mutations in PRF1. We have recently described a significant increase in the subpopulation of CD8 + T cells with clonal expansion and CD5 down-regulation in Epstein-Barr virus associated-HLH, which represented a valuable tool for its diagnosis. However, this unusual phenotype of CD8 + T cells has not been investigated fully in patients with FHL2. We performed immunophenotypic analysis of peripheral blood and measured serum proinflammatory cytokines in 5 patients with FHL2. All patients showed significantly increased subpopulations of activated CD8 + T cells with down-regulation of CD5, which were negligible among normal controls. Analysis of T-cell receptor Vβ repertoire suggested the reactive and oligoclonal expansion of these cells. The proportion of the subset declined after successful treatment concomitant with reduction in the serum levels of cytokines in all patients except one who continued to have a high proportion of the subset and died. These findings suggest that down-regulation of CD5 on activated CD8 +

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“…It physically associates with the TCR [30] and the B-cell receptor [31] and functions as positive or negative regulator of antigen receptor signaling, depending on the cell type analyzed and its maturation stage [32]. Upon CD3 ligation, the CD5 cytoplasmic tail becomes phosphorylated leading to the likely recruitment of p56 lck [33], PI3K [34], proto-oncoprotein c-Cbl, ras GTPase-activating protein [35] and SHP-1 [36].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2009

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It has been suggested that high affinity/avidity interactions are required for the thymic selection of Treg. Here, we investigated the role of CD5, a negative regulator of TCR signaling, in the selection and function of ''naturally occurring'' CD4 1 CD25 1 Treg (nTreg). Analysis of CD5 À/À mice showed a significant increase in the percentage and absolute numbers of CD4 1 CD25 1 Foxp3 1 thymocytes and peripheral T lymphocytes, compared with BALB/c mice. Thymi from CD5 À/À mice showed reduced cellularity due to increased apoptosis, which preferentially affected naïve T cells. To characterize nTreg selection at the molecular level we investigated the phosphorylation of Erk, c-Cbl, PI3K and Akt. CD5 À/À nTreg showed increased basal levels of p-Erk compared with wild-type nTreg. Interestingly, in response to CD3 plus CD28 costimulation, CD5 À/À naïve T cells but not CD5 À/À nTreg showed lower levels of p-Akt. Finally, CD5 À/À nTreg were thymus-derived and fully functional. We conclude that the enrichment of nTreg observed in the absence of CD5 signaling is due to de novo generation of nTreg and selective reduction of CD4 1 CD25 À naïve thymocytes. Furthermore, we provide new evidence supporting a potential role of CD5 in thymocyte survival, through a mechanism that may involve the phosphorylation of Akt.Key words: CD5 . Development . Treg . Signaling . Thymocyte IntroductionThe maintenance of immunological self-tolerance is a fundamental property of the immune system besides the clearance of pathogenic agents. Central and peripheral mechanisms exist to ensure the elimination or inactivation of potentially harmful autoreactive T cells. Negative selection in the thymus induces the deletion of most self-reactive T-cell clones during T-cell development [1]. However, some autoreactive T cells escape from clonal deletion and need to be controlled by peripheral mechanisms including peripheral T-cell deletion by activation-induced cell death [2], T-cell anergy [3] and T-cell-mediated suppression [4].Recently, non-deletional mechanisms of central tolerance have been re-evaluated, such as the development of thymus-derived Treg [5]. These cells are currently known as ''naturally occurring'' CD4 1 CD25 1 Treg (nTreg), which represent a small population (5-10%) of peripheral CD4 1 T cells and are characterized by high levels of surface CD25 and by the expression of Foxp3, a transcription factor, identified as a key regulator of nTreg development and function [6]. In addition, nTreg also express activation markers such 2233as CTLA-4, glucocorticoid-induced tumor necrosis factor receptor (GITR), CD62L, OX40 and CD103 [7,8]. nTreg were first studied for their role in maintaining self-tolerance [9], preventing autoimmune diseases [10] and the development of harmful immunopathological responses [11]. However, nTreg can also participate in modulating adaptive immunity to viruses, bacteria and parasites affecting favorably or detrimentally the outcome of immune responses to infections [12,13].The mechanisms of suppression used by Treg...

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CD5 Signal Transduction: Positive or Negative Modulation of Antigen Receptor Signaling

Cited by 60 publications

References 0 publications

CD6 binds to pathogen-associated molecular patterns and protects from LPS-induced septic shock

CD6 binds to pathogen-associated molecular patterns and protects from LPS-induced septic shock

Down-regulation of CD5 expression on activated CD8+ T cells in familial hemophagocytic lymphohistiocytosis with perforin gene mutations

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

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CD5 Signal Transduction: Positive or Negative Modulation of Antigen Receptor Signaling

Cited by 60 publications

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CD6 binds to pathogen-associated molecular patterns and protects from LPS-induced septic shock

CD6 binds to pathogen-associated molecular patterns and protects from LPS-induced septic shock

Down-regulation of CD5 expression on activated CD8+ T cells in familial hemophagocytic lymphohistiocytosis with perforin gene mutations

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

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