Analysis of regulatory CD8 T cells in Qa-1-deficient mice

Hu, Dan; Ikizawa, Koichi; Lu, Linrong; Sanchirico, Marie E.; Shinohara, Mari L.; Cantor, Harvey

doi:10.1038/ni1063

Cited by 308 publications

(290 citation statements)

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“…Generation and analysis of Qa-1-deficient mice several years ago has allowed further definition of the role of Qa-1 in the generation and mediation of suppressive activity by this CD8 + Treg subset. Mice lacking Qa-1-restricted CD8 + Treg develop exaggerated immune responses to self antigen (21). However, Qa-1-deficient mice have not been sufficient to fully define the contribution of Qa-1-restricted CD8 + T cells to immunological suppression, because of the bivalent interaction of Qa-1 with its receptors.…”

Section: Qa-1-restricted Cd8 + Tregmentioning

confidence: 99%

“…As a result, the immune response phenotype of Qa-1-deficient mice reflects two opposing effects. Enhanced CD4-dependent immunity reflects loss of the Qa-1 target for CD8 + Treg activity (21), while reduced CD4-dependent immunity results from lysis of activated CD4 + cells by NK cells that are unencumbered by an inhibitory NKG2A-Qa-1/Qdm interaction (24).…”

Section: Qa-1-restricted Cd8 + Tregmentioning

confidence: 99%

“…The most efficient system for generating CD8 + Treg occurs during the induction of EAE, at which CD8 suppressive activity develops during the primary immunization and can prevent subsequent induction of disease in the same host (21). Other approaches include T-cell vaccination (TCV), immunization with Qa-1-restricted peptide or DC loaded with such peptides (28,35).…”

Section: Induction (Priming) Of Cd8 + Tregmentioning

confidence: 99%

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Generation and Regulation of CD8+ Regulatory T Cells

Cantor

2008

Cell Mol Immunol

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Section: Qa-1-restricted Cd8 + Tregmentioning

confidence: 99%

Section: Qa-1-restricted Cd8 + Tregmentioning

confidence: 99%

Section: Induction (Priming) Of Cd8 + Tregmentioning

confidence: 99%

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Generation and Regulation of CD8+ Regulatory T Cells

Cantor

2008

Cell Mol Immunol

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“…24 Single splenic cell suspensions were prepared, and red blood cells were lysed. Spleen cells were incubated at 41C for 45 min with rat anti-CD8 þ or anti-CD4 þ antibody (BD Pharmingen).…”

Section: Depletion Of Immune Cell Subsetsmentioning

confidence: 99%

Humoral and cellular immunity induced by tumor cell vaccine based on the chicken xenogeneic homologous matrix metalloproteinase-2

Tian

et al. 2006

Cancer Gene Ther

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Matrix metalloproteinase-2 (MMP-2) has been used as a target for cancer immunotherapy. The activation of immunization by breaking immune tolerance to self-MMP-2 may be one of the promising approaches for the treatment of MMP-2-positive tumors. In this study, we constructed the xenogeneic tumor cell vaccine c-MMP-2 by transfecting CT26 and LLC cells with chicken MMP-2 cDNA constructs. MMP-2-specific autoantibodies in sera and tumor cells were found in mice immunized with c-MMP-2. Protection against tumor growth was evaluated in respect of the relative contributions of autoantibodies, CD4 þ , and CD8 þ T cells. Treatment with this vaccine (c-MMP-2) also prolonged the survival time of mice bearing cancer. The specific cytotoxic T-cell responses suggested that the treatment increased CD8 þ T-cell activity. The antitumor activity of c-MMP-2 was abrogated by in vivo depletion of CD4 þ and CD8 þ T-lymphocytes and improved by adoptive transfer of CD4 þ and CD8 þ T-lymphocytes from the mice treated with c-MMP-2. An alternative DNA vaccination strategy for cancer therapy was identified in this study by eliciting humoral and cellular immunoresponse with a crossreacting transfectant.

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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%

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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Analysis of regulatory CD8 T cells in Qa-1-deficient mice

Cited by 308 publications

References 42 publications

Generation and Regulation of CD8+ Regulatory T Cells

Generation and Regulation of CD8+ Regulatory T Cells

Humoral and cellular immunity induced by tumor cell vaccine based on the chicken xenogeneic homologous matrix metalloproteinase-2

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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Analysis of regulatory CD8 T cells in Qa-1-deficient mice

Cited by 308 publications

References 42 publications

Generation and Regulation of CD8+ Regulatory T Cells

Generation and Regulation of CD8+ Regulatory T Cells

Humoral and cellular immunity induced by tumor cell vaccine based on the chicken xenogeneic homologous matrix metalloproteinase-2

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