Negative regulation of antigen receptor-mediated signaling by constitutive asociation of CD5 with the SHP-1 protein tyrosine phosphatase in B-1 B cells

Sen, Goutam; Bikah, Gabriel; Venkataraman, Chandrasekhar; Bondada, Subbarao

doi:10.1002/(sici)1521-4141(199910)29:10<3319::aid-immu3319>3.3.co;2-0

Cited by 41 publications

(47 citation statements)

References 22 publications

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“…This negative signaling of CD5 occurs via a protein tyrosine phosphatase, SHP-1 that is recruited to the cytoplasmic domain of CD5 upon T cell activation (35). We hypothesized that lack of CD5 expression might remove negative effects of CD5 on TCR signaling and thus enhance T reg function, which is known to be TCR dependent.…”

Section: Cd4 + Cd25 + T Reg Cells From Cd5 −/− Mice Are More Potent Imentioning

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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Section: Cd4 + Cd25 + T Reg Cells From Cd5 −/− Mice Are More Potent Imentioning

confidence: 99%

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

et al. 2008

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“…Pani et al [75] have since established an association between the BCR and the src-homology 2 domain-containing protein tyrosine phosphatase (SHP)-1, so that cross-linking of the BCR results in an immediate dissociation of SHP-1. Furthermore, SHP-1 has recently been demonstrated in humans [76] to be constitutively associated with the BCR, at least in part, through the immunoregulatory tyrosine-based inhibitory motif (ITIM) of CD5. This indicates that CD5 negatively regulates BCRinitiated growth signalling by recruiting additional SHP-1 into the vicinity of the BCR, or stabilizing the complex.…”

Section: Role Of Polymorphism In Signalling Molecules In Determining mentioning

confidence: 99%

Recent Progress in the Understanding of B‐Cell Functions in Autoimmunity

Porakishvili

Mageed

Jamin³

et al. 2001

Scand J Immunol

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54:30±38Our early concepts of the normal role of B cells in immunity focused on their ability to produce antibodies (Ab) and in the case of autoimmune diseases autoAbs, some of which were pathogenic. Over the past 10 years, it has became apparent that B cells display a variety of characteristics, other than Ab production, which could contribute to autoimmunity. They normally play a role in the development of lymphoid architecture, regulating T-cell subsets and dendritic cell (DC) function through cytokine production, and in activation of T cells. Receptors editing is also important in B cells which aids in immunity to infection and, possibly, prevention of autoimmunity. Transgenic animal models have now shown that B cells are necessary for many autoimmune diseases although their Ab products are not required in some cases. Negative signalling by CD5 and other molecules, such as CD22, in maintaining tolerance through recruitment of src-homology two domaincontaining protein tyrosine phosphatase-1 has also been documented. In fact, we have now reached a new era whereby the B cell has returned as an important contributor to autoimmune disorders, so that the race is on to characterize signalling regulation via the B-cell receptor and coreceptors. Identification of such molecules and their potential defects should lead to effective ways of controlling the immune response and in particular preventing the development of autoimmune states. The classical view of B cells in the biology of immune responses to infectious and self-antigens (Ag) that they promote immunity primarily by producing Ab turns out to be rather naõ Ève. Indeed, studies over the last few years indicate that this view is far from complete, and suggest that B lymphocytes have extraordinarily diverse functions within the immune system. Furthermore, it is becoming increasingly clear that the pathogenesis of autoimmune diseases cannot solely be accounted for by T cells, and intrinsic abnormalities of B cells have been described in such conditions. In this brief review we highlight some recent observations in the context of B lymphocyte in pathophysiology, and focus on their revival as pivotal players the pathophysiology in autoimmune diseases. Yet, it remains difficult to provide a model of how important B cells are in immunity and autoimmunity.

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“…B-1 cells express high levels of IgM and low levels of IgD and B220, lack CD23, and when found in the peritoneum, express the macrophage marker CD11b (Mac-1). Many B-1 cells (termed B-1a) also express CD5, and it has been proposed that this coreceptor may contribute to the unique characteristics of these cells (5)(6)(7)(8). CD5 ϩ B-1 cells have been shown to display an altered responsiveness to BCR ligation compared with their B-2 cohorts.…”

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“…CD5 ϩ B-1 cells have been shown to display an altered responsiveness to BCR ligation compared with their B-2 cohorts. This is marked by a diminished ability for intracellular Ca 2ϩ mobilization, aberrant proliferation, and increased apoptosis after BCR cross-linking (6,7,9,10). While B-1 cells only comprise a small percentage of all B cells, they are the primary source of the serum Ab in unimmunized mice, known as natural Ab (3,11,12).…”

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confidence: 99%

The Unique Antigen Receptor Signaling Phenotype of B-1 Cells Is Influenced by Locale but Induced by Antigen

Chumley

Porto

Cambier

2002

The Journal of Immunology

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Normal animals contain an autoreactive B lymphocyte subset, the B-1 subset, which is controlled by undefined mechanisms to prevent autoimmunity. Using a VH11Vκ9 Ig transgenic mouse, with a specificity prototypic of the subset, we have explored conditions responsible for the previously reported Ag hyporesponsiveness of these cells. We report that peritoneal VH11Vκ9 B cells exhibit typical B-1 behavior with high basal intracellular free Ca2+ and negligible receptor-mediated calcium mobilization. However, splenic B cells from this mouse, while phenotypically similar to their peritoneal counterparts, including expression of CD5, mount robust B-2-like responses to Ag as measured by calcium influx and altered tyrosine phosphorylation responses. When these splenic cells are adoptively transferred to the peritoneal cavity and encounter their cognate self-Ag, they acquire a B-1 signaling phenotype. The ensuing hyporesponsiveness is characterized by increases in both basal intracellular calcium and resting tyrosyl phosphorylation levels and is highlighted by a marked abrogation of B cell receptor-mediated calcium mobilization. Thus, we show that self-Ag recognition in specific microenvironments such as the peritoneum, and we would propose other privileged sites, confers a unique form of anergy on activated B cells. This may explain how autoreactive B-1 cells can exist while autoimmunity is avoided.

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Negative regulation of antigen receptor-mediated signaling by constitutive asociation of CD5 with the SHP-1 protein tyrosine phosphatase in B-1 B cells

Cited by 41 publications

References 22 publications

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

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

Recent Progress in the Understanding of B‐Cell Functions in Autoimmunity

The Unique Antigen Receptor Signaling Phenotype of B-1 Cells Is Influenced by Locale but Induced by Antigen

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