Chronic Exposure to Low Levels of Antigen in the Periphery Causes Reversible Functional Impairment Correlating with Changes in CD5 Levels in Monoclonal CD8 T Cells

Stamou, Panagiota; Jersey, James de; Carmignac, Danielle; Mamalaki, Clio; Kioussis, Dimitris; Stockinger, Brigitta

doi:10.4049/jimmunol.171.3.1278

Cited by 56 publications

(59 citation statements)

References 46 publications

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“…The lack of T cell activation indicated by the decrease in CD69 expression despite the persistence of a cognate ligand is consistent with this suggestion. Likewise, so is the finding, similar to others (37), that expression of the inhibitory signaling molecule CD5 (46,47) was increased on residual CD8 ϩ T cells in 11c.OVA mice. Further studies will be required to determine the fate of unresponsive T cells in the face of persistent constitutive expression of cognate Ag by resting DC and whether these cells survive for long periods of time as reported in other models (48,49).…”

Section: Discussionsupporting

confidence: 81%

“…The expression of CD5, an inhibitory signaling molecule, is a marker of the "anergic" state induced in CD8 ϩ T cells exposed to persistent antigenic stimulation (37). We found a significantly higher ( p Ͻ 0.01) level of CD5 expression on OT-I cells in 11c.OVA compared with nontransgenic control mice or in anti-CD40 mAb-treated 11c.OVA mice (containing effector OT-I cells) measured either 7 (not shown) or 21 days after transfer (Table I).…”

Section: Residual Ova-specific Cd8 ϩ T Cells In 11cova Mice Are Unrementioning

confidence: 62%

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Cognate CD4+ Help Elicited by Resting Dendritic Cells Does Not Impair the Induction of Peripheral Tolerance in CD8+ T Cells

Steptoe

Ritchie

Wilson

et al. 2007

The Journal of Immunology

104

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Peripheral tolerance is required to prevent autoimmune tissue destruction by self-reactive T cells that escape negative selection in the thymus. One mechanism of peripheral tolerance in CD8+ T cells is their activation by resting dendritic cells (DC). In contrast, DC can be “licensed” by CD4+ T cells to induce cytotoxic function in CD8+ T cells. The question that then arises, whether CD4+ T cell help could impair peripheral tolerance induction in self-reactive CD8+ T cells, has not been addressed. In this study we show that CD4+ T cell activation by resting DC results in helper function that transiently promotes the expansion and differentiation of cognate CD8+ T cells. However, both the CD4+ and CD8+ T cell populations ultimately undergo partial deletion and acquire Ag unresponsiveness, disabling their ability to destroy OVA-expressing pancreatic β cells and cause diabetes. Thus, effective peripheral tolerance can be induced by resting DC in the presence of CD4+ and CD8+ T cells with specificity for the same Ag.

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Section: Discussionsupporting

confidence: 81%

Section: Residual Ova-specific Cd8 ϩ T Cells In 11cova Mice Are Unrementioning

confidence: 62%

Cognate CD4+ Help Elicited by Resting Dendritic Cells Does Not Impair the Induction of Peripheral Tolerance in CD8+ T Cells

Steptoe

Ritchie

Wilson

et al. 2007

The Journal of Immunology

104

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“…In the BM transfer setting, ;30-40% of DCs express OVA and, accordingly, OT-I expression of PD-1 and CD5 is reduced compared with OT-I T cells transferred to 11c.OVA mice, where all DCs express OVA. This is consistent with previous reports that T-cell tuning is dependent on antigen expression levels (35,36). The data also indicate that inactivation is effective even when antigen is expressed by a minority of all DCs.…”

Section: Discussionsupporting

confidence: 93%

Antigen-Encoding Bone Marrow Terminates Islet-Directed Memory CD8+ T-Cell Responses to Alleviate Islet Transplant Rejection

et al. 2016

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Islet-specific memory T cells arise early in type 1 diabetes (T1D), persist for long periods, perpetuate disease, and are rapidly reactivated by islet transplantation. As memory T cells are poorly controlled by "conventional" therapies, memory T cell-mediated attack is a substantial challenge in islet transplantation, and this will extend to application of personalized approaches using stem cell-derived replacement b-cells. New approaches are required to limit memory autoimmune attack of transplanted islets or replacement b-cells. Here, we show that transfer of bone marrow encoding cognate antigen directed to dendritic cells, under mild, immune-preserving conditions, inactivates established memory CD8 + T-cell populations and generates a long-lived, antigen-specific tolerogenic environment. Consequently, CD8 + memory T cell-mediated targeting of islet-expressed antigens is prevented and islet graft rejection alleviated. The immunological mechanisms of protection are mediated through deletion and induction of unresponsiveness in targeted memory T-cell populations. The data demonstrate that hematopoietic stem cell-mediated gene therapy effectively terminates antigenspecific memory T-cell responses, and this can alleviate destruction of antigen-expressing islets. This addresses a key challenge facing islet transplantation and, importantly, the clinical application of personalized b-cell replacement therapies using patient-derived stem cells.

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“…Introduction of transgenic CD5 into CD5 −/− mice but not that encoding a truncated form of CD5 protein was able to rescue the CD5 −/− phenotype demonstrating the absolute requirement of the cytoplasmic tail of CD5 for its inhibitory function of TCR signaling in thymocytes (26). CD5 has also been shown to have a role in T cell anergy induced by chronic antigen exposure (27). More recently, in a model of T cell tolerance induced by antigen targeted to dendritic cells, the T cell unresponsiveness was linked to increased CD5 expression (28).…”

Section: Introductionmentioning

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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Chronic Exposure to Low Levels of Antigen in the Periphery Causes Reversible Functional Impairment Correlating with Changes in CD5 Levels in Monoclonal CD8 T Cells

Cited by 56 publications

References 46 publications

Cognate CD4+ Help Elicited by Resting Dendritic Cells Does Not Impair the Induction of Peripheral Tolerance in CD8+ T Cells

Cognate CD4+ Help Elicited by Resting Dendritic Cells Does Not Impair the Induction of Peripheral Tolerance in CD8+ T Cells

Antigen-Encoding Bone Marrow Terminates Islet-Directed Memory CD8+ T-Cell Responses to Alleviate Islet Transplant Rejection

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

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