The role of CD8<sup>+</sup>CD28<sup>−</sup>regulatory cells in suppressing myasthenia gravis-associated responses by a dual altered peptide ligand

Ben-David, Hava; Sharabi, Amir; Dayan, Molly; Sela, Michael; Mozes, Edna

doi:10.1073/pnas.0708577104

Cited by 47 publications

(41 citation statements)

References 42 publications

(42 reference statements)

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“…[37][38][39] CD8 ϩ FoxP3 ϩ T reg occur in negligible numbers in naive mice, which makes isolation and subsequent characterization of viable cells impossible. 9 Naturally occurring CD8 regulatory T-cell populations have been identified on the basis of surface markers and have been shown to be regulatory in several autoimmune diseases, including systemic lupus erythematosus, 40 experimental autoimmune encephalitis, 41,42 and myasthenia gravis 43 and to induce tolerance after solid organ transplantation. 44 However, these cells have not been demonstrated to express FoxP3 in vivo and are sometimes present without having suppressive capacity.…”

Section: Discussionmentioning

confidence: 99%

Identification and expansion of highly suppressive CD8+FoxP3+ regulatory T cells after experimental allogeneic bone marrow transplantation

Robb

Lineburg

Kuns

et al. 2012

Blood

118

116

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FoxP3 ؉ confers suppressive properties and is confined to regulatory T cells (T reg ) that potently inhibit autoreactive immune responses. In the transplant setting, natural CD4 ؉ T reg are critical in controlling alloreactivity and the establishment of tolerance. We now identify an important CD8 ؉ population of FoxP3 ؉ T reg that convert from CD8 ؉ conventional donor T cells after allogeneic but not syngeneic bone marrow transplantation. These CD8 ؉ T reg undergo conversion in the mesenteric lymph nodes under the influence of recipient dendritic cells and TGF-␤. Importantly, this population is as important for protection from GVHD as the well-studied natural CD4 ؉ FoxP3 ؉ population and is more potent in exerting class I-restricted and antigen-specific suppression in vitro and in vivo. Critically, CD8 ؉ FoxP3 ؉ T reg are exquisitely sensitive to inhibition by cyclosporine but can be massively and specifically expanded in vivo to prevent GVHD by coadministering rapamycin and IL-2 antibody complexes. CD8 ؉ FoxP3 ؉ T reg thus represent a new regulatory population with considerable potential to preferentially subvert MHC class I-restricted T-cell responses after bone marrow transplantation. (Blood. 2012;119(24): 5898-5908) IntroductionThe development of GVHD remains a major limitation to the therapeutic potential of bone marrow transplantation (BMT). GVHD occurs as a result of immunologic damage to the host tissue by conventional T and NK cells in the transplanted donor graft. Natural regulatory T cells (T reg ) are defined by the expression of FoxP3 1 and are dedicated to suppression of immune responses. The importance of CD4 ϩ FoxP3 ϩ T reg in peripheral tolerance is well established, and the presence of naturally occurring CD4 ϩ T reg makes them an attractive target for adoptive transfer to control pathologic immune responses. Consequently, studies in GVHD using freshly isolated or ex vivo expanded donor CD4 ϩ T reg have demonstrated a delay or prevention of GVHD. [2][3][4][5] Conversely, depletion of CD4 ϩ T reg from the donor graft results in an increased severity of GVHD. 2 A limitation to using naive T reg in the adoptive transfer setting is the high ratio required compared with FoxP3 Ϫ cells in the ingoing graft (1:1); thus, the number of T reg required is restrictive. This has resulted in difficulties transferring adoptive cell therapy into the clinic with multiple groups now focusing on ex vivo expansion protocols in an endeavor to overcome this limitation. [6][7][8] In contrast to the extensive research being completed on naive CD4 ϩ T reg , studies investigating the role of T reg undergoing conversion in the periphery after BMT are lacking. The identification of FoxP3 as a T reg marker 1 and subsequent development of reagents that allow for identification (B6.FoxP3-GFP), 9 tracking (B6.FoxP3.LuciDTR) 10 and depletion (B6.DEREG) 11 of these cells has allowed for a more thorough investigation. We have used these reagents to characterize T reg populations after transplantation with the aim of identifying m...

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Section: Discussionmentioning

confidence: 99%

Identification and expansion of highly suppressive CD8+FoxP3+ regulatory T cells after experimental allogeneic bone marrow transplantation

Robb

Lineburg

Kuns

et al. 2012

Blood

118

116

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“…The competence of all types of Tregs to modulate immune responses and maintain self-tolerance requires not only a sufficient numerical mass and functional suppressive abilities but also the orchestration of the various types of cells (13). CD8 Tregs, in addition to CD4 Tregs, constitute a major cell population that has been demonstrated to play an important role in autoimmune diseases, including experimental autoimmune encephalomyelitis (14), myasthenia gravis (15), and SLE (16). In SLE patients, the number of CD8 ϩ cells is reduced and the generation of suppressive CD8 cells is considerably limited (16).…”

Section: S Ystemic Lupus Erythematosus (Sle)mentioning

confidence: 99%

The Suppression of Murine Lupus by a Tolerogenic Peptide Involves Foxp3-Expressing CD8 Cells That Are Required for the Optimal Induction and Function of Foxp3-Expressing CD4 Cells

Sharabi

Mozes

2008

The Journal of Immunology

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A peptide, designated human CDR1 (hCDR1), that is based on the CDR1 of an anti-DNA Ab ameliorates systemic lupus erythematosus (SLE) in murine models via the induction of CD4+CD25+ regulatory T cells (Tregs). In the present study, the involvement of CD8 Tregs in the mode of action of hCDR1 was investigated in SLE-afflicted (NZB × NZW)F1 mice and in SJL mice following immunization with the lupus-inducing anti-DNA mAb that bears a common Id, 16/6Id. Treatment with hCDR1 up-regulated Foxp3-expressing CD8+CD28− Tregs in association with clinical amelioration of lupus manifestations. Furthermore, the in vivo depletion of the latter cells diminished the clinical improvement and the inhibitory effects of hCDR1 on the secretion of IFN-γ and resulted in the up-regulation of IL-10. However, the stimulatory effect of hCDR1 on the secretion of TGF-β was not affected by the CD8 Tregs. In the absence of CD8 Tregs, CD4+CD25+ Tregs were unable to expand in the hCDR1-treated mice, and the expression of Foxp3 was reduced, thereby interfering further with the suppressive function of CD4+CD25+ Tregs as determined in the in vitro assays. However, CD8 cells from hCDR1-treated mice that were adoptively transferred into SLE-afflicted mice led to up-regulation of CD4+CD25+ cells with intensified Foxp3 expression in the recipient mice. Thus, a functional link between two subsets of Tregs is demonstrated in which CD8+CD28− Tregs are required for both the optimal expansion and function of lupus ameliorating hCDR1-induced CD4+CD25+ Tregs.

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“…In addition, GITR can be activated by progesterone receptor (Nelson et al, 1999 andKanamaru et al, 2004) and possibly progesterone acts on Treg cells by upregulating GITR among other effects. Interestingly, in studies experimenting EAMG animals, the treatment of analogs of myasthenogenic peptides notably demonstrated a decrease in lymph node proliferation as well as a decrease of INF involving the action of CD8+ Tregs (Ben-David et al, 2007). Newborn can develop neonatal MG and is observed in around 10 % of mother holding the burden of the disease (Beekman etal., 1997).…”

Section: Modulation Effects Of Pregnancy In Myasthenia Gravis Mothersmentioning

confidence: 99%

Mechanism of Autoimmunity in Pregnancy - The Good and the Bad

Tajouri

Brenu

Staines³

et al. 2011

Autoimmune Disorders - Pathogenetic Aspects

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The role of CD8⁺CD28⁻regulatory cells in suppressing myasthenia gravis-associated responses by a dual altered peptide ligand

Cited by 47 publications

References 42 publications

Identification and expansion of highly suppressive CD8+FoxP3+ regulatory T cells after experimental allogeneic bone marrow transplantation

Identification and expansion of highly suppressive CD8+FoxP3+ regulatory T cells after experimental allogeneic bone marrow transplantation

The Suppression of Murine Lupus by a Tolerogenic Peptide Involves Foxp3-Expressing CD8 Cells That Are Required for the Optimal Induction and Function of Foxp3-Expressing CD4 Cells

Mechanism of Autoimmunity in Pregnancy - The Good and the Bad

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The role of CD8+CD28−regulatory cells in suppressing myasthenia gravis-associated responses by a dual altered peptide ligand

Cited by 47 publications

References 42 publications

Identification and expansion of highly suppressive CD8+FoxP3+ regulatory T cells after experimental allogeneic bone marrow transplantation

Identification and expansion of highly suppressive CD8+FoxP3+ regulatory T cells after experimental allogeneic bone marrow transplantation

The Suppression of Murine Lupus by a Tolerogenic Peptide Involves Foxp3-Expressing CD8 Cells That Are Required for the Optimal Induction and Function of Foxp3-Expressing CD4 Cells

Mechanism of Autoimmunity in Pregnancy - The Good and the Bad

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The role of CD8⁺CD28⁻regulatory cells in suppressing myasthenia gravis-associated responses by a dual altered peptide ligand