Regulatory functions of CD8+CD28– T cells in an autoimmune disease model

Najafian, Nader; Chitnis, Tanuja; Salama, Alan D.; Zhu, Bing; Benou, Christina; Yuan, Xin; Clarkson, Michael R.; Sayegh, Mohamed H.; Khoury, Samia J.

doi:10.1172/jci17935

Cited by 236 publications

(178 citation statements)

References 57 publications

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“…Several subsets of natural CD8 Tregs have been identified based on the expression of CD25 [69], FoxP3 [70,71], CD122 [72] and/or HLA-G [73], or lack of CD28 expression [74]. CD8+CD122+ abTCR Tregs could sense activated T cells by interacting with cell surface molecules including classical MHC class I [75] and directly constrain proliferation and IFN-c production of CD8 T cells presumably via production of IL-10 [76].…”

Section: Generalitiesmentioning

confidence: 99%

Role of CD8 T cell subsets in the pathogenesis of multiple sclerosis

et al. 2011

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a b s t r a c tMultiple sclerosis (MS) is an immune-mediated disease of the central nervous system leading to demyelination and axonal/neuronal loss. Cumulating evidence points to a key role for CD8 T cells in this disabling disease. Oligoclonal CD8 T cells reside in demyelinating plaques where they are likely to contribute to tissue destruction. Histopathological analyses and compelling observations from animal models indicate that cytotoxic CD8 T cells target neural cell populations with the potential of causing lesions reminiscent of MS. However, CD8 T cell differentiation results in several subsets of effector CD8 T cells that could be differentially implicated in the mechanisms contributing to tissue damage. Moreover CD8 regulatory T cells arise as important populations involved in restoring immune homoeostasis and in maintaining immune privileged sites. Here we examine the current literature pertaining to the role of CD8 effector and regulatory T cell subsets in the pathogenesis of MS.

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Section: Generalitiesmentioning

confidence: 99%

Role of CD8 T cell subsets in the pathogenesis of multiple sclerosis

et al. 2011

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“…Several cell surface molecules have been associated with CD8 + Treg in different experimental systems. For example, CD8 + CD28 -cells behave as regulatory T cells, since transfer of these cells (but not CD28 + cells) into CD8-deficient mice significantly suppressed EAE (13). Moreover, CD8 + CD28 -but not CD8 + CD28 + cells also inhibited IFN- production of myelin oligodendrocyte glycoprotein (MOG)-specific CD4 + T cells through an interaction that required cell-cell contact.…”

Section: Definition Of Cd8 + Tregmentioning

confidence: 99%

Generation and Regulation of CD8+ Regulatory T Cells

Cantor

2008

Cell Mol Immunol

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“…The vast majority of Foxp3 1 T cells are confined to TCR-ab 1 CD4 1 T cells, and little is known about CD8 1 T cells expressing Foxp3. Certain surface phenotypes such as CD28 À [7], CD122 1 [8], CD8aa 1 [9, 10], latencyassociated peptide (LAP) 1 [11] and restriction to the nonclassical MHCI molecule Qa-1 [12] have been linked with immunosuppressive functions of CD8 1 T cells. However, Foxp3 expression was either absent in these populations [8,9,[13][14][15] …”

mentioning

confidence: 99%

“…3C). CD122 expression and lack of CD28 expression were previously used to define naturally occurring CD8 1 Treg populations [7,8]. To assess on a protein level whether these populations relate to the here described Foxp3 1 T-cell population, we compared CD122 and CD28 expression between CD8 1 Foxp3 1 -gated T-cell populations ex vivo and in vitro.…”

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confidence: 99%

CD8⁺Foxp3⁺ T cells share developmental and phenotypic features with classical CD4⁺Foxp3⁺ regulatory T cells but lack potent suppressive activity

et al. 2011

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''Suppressor T cells'' were historically defined within the CD8 1 T-cell compartment and recent studies have highlighted several naturally occurring CD8 1 Foxp3 À Treg populations. However, the relevance of CD8 1 Foxp3 1 T cells, which represent a minor population in both thymi and secondary lymphoid organs of nonmanipulated mice, remains unclear. We here demonstrate that de novo Foxp3 induction in peripheral CD8 1 Foxp3 À T cells is counter-regulated by DC-mediated co-stimulation via CD80/CD86. CD8 1 Foxp3 1 T cells fail to develop in TCR-transgenic mice with Rag1 À/À background, similar to classical CD4 1 Foxp3 1 Tregs. Notably, both naturally occurring and induced CD8 1 Foxp3 1 T cells express bona fide Treg markers including CD25, GITR, CTLA4 and CD103, and show defective IFN-c production upon restimulation when compared with their CD8 1 Foxp3 À counterparts. However, utilizing DEREG transgenic mice for the isolation of Foxp3 1 cells by eGFP reporter expression, we demonstrate that induced CD8 1 Foxp3 1 T cells similar to activated CD8 1 Foxp3 À T cells only mildly suppress T-cell proliferation and IFN-c production. We therefore categorize CD8 1 Foxp3 1 T cells as a tightly controlled population sharing certain developmental and phenotypic properties with classical CD4 1 Foxp3 1 Tregs, but lacking potent suppressive activity.Keywords: CD8 . Foxp3 . TGF-b . Treg Supporting Information available online IntroductionFoxp3 is a master regulator of CD4 1 Treg function [1][2][3] and its mutation or the depletion of Foxp3 1 cells led to onset of multiorgan autoimmunity [4][5][6]. The vast majority of Foxp3 1 T cells are confined to TCR-ab 1 CD4 1 T cells, and little is known about CD8 1 T cells expressing Foxp3. Certain surface phenotypes such as CD28 À [7], CD122 1 [8], CD8aa 1 [9, 10], latencyassociated peptide (LAP) 1 [11] and restriction to the nonclassical MHCI molecule Qa-1 [12] have been linked with immunosuppressive functions of CD8 1 T cells. However, Foxp3 expression was either absent in these populations [8,9,[13][14][15] 716with the defining surface phenotype [11] or was not investigated specifically on a protein level [16]. Additionally, the isolation of viable CD8 1 Foxp3 1 populations was hampered by the nuclear localization of Foxp3 in conjunction with the occurrence of these cells at low numbers in nonmanipulated mice [2,17], rendering the identity and relevance of mouse CD8 1 Foxp3 1 T cells unclear.Classical CD4 1 Foxp3 1 Tregs develop either intrathymically (natural Tregs, nTregs) or in the periphery via conversion from Foxp3 À T cells (induced Tregs). Specialized dendritic cells (DC) can initiate the latter process by providing the key factors TGF-b and all-trans-retinoic acid (RA) [18,19]. Although natural and in vitro induced CD4 1 Foxp3 1 Tregs share key phenotypic and functional characteristics, they differ in the stability of Foxp3 expression, and different degrees of demethylation of an evolutionarily conserved region within the foxp3 locus (TSDR; Treg-specific demethylated region) have b...

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Regulatory functions of CD8+CD28– T cells in an autoimmune disease model

Cited by 236 publications

References 57 publications

Role of CD8 T cell subsets in the pathogenesis of multiple sclerosis

Role of CD8 T cell subsets in the pathogenesis of multiple sclerosis

Generation and Regulation of CD8+ Regulatory T Cells

CD8⁺Foxp3⁺ T cells share developmental and phenotypic features with classical CD4⁺Foxp3⁺ regulatory T cells but lack potent suppressive activity

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Regulatory functions of CD8+CD28– T cells in an autoimmune disease model

Cited by 236 publications

References 57 publications

Role of CD8 T cell subsets in the pathogenesis of multiple sclerosis

Role of CD8 T cell subsets in the pathogenesis of multiple sclerosis

Generation and Regulation of CD8+ Regulatory T Cells

CD8+Foxp3+ T cells share developmental and phenotypic features with classical CD4+Foxp3+ regulatory T cells but lack potent suppressive activity

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CD8⁺Foxp3⁺ T cells share developmental and phenotypic features with classical CD4⁺Foxp3⁺ regulatory T cells but lack potent suppressive activity