CD8+ Tregs in lupus, autoimmunity, and beyond

Dinesh, Ravi; Skaggs, Brian J.; Cava, Antonio La; Hahn, Bevra H.; Singh, Ram Pyare

doi:10.1016/j.autrev.2010.03.006

Cited by 116 publications

(90 citation statements)

References 151 publications

(183 reference statements)

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“…Human CD8 + T cells from tolerant, but not control mice exhibited suppressor activity and high expression of BCL6. These data are consistent with recent studies emphasizing the role of CD8 + Ts cells in autoimmunity, transplantation, and infectious diseases (39)(40)(41)(42).…”

Section: Discussionsupporting

confidence: 82%

BCL6 Is Required for Differentiation of Ig-Like Transcript 3-Fc–Induced CD8+ T Suppressor Cells

Chang

Vlad²,

D’Agati³

et al. 2010

The Journal of Immunology

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Ig-like transcript 3 (ILT3) is an inhibitory receptor expressed by tolerogenic dendritic cells. When human CD8+ T cells are allostimulated in the presence of recombinant ILT3-Fc protein, they differentiate into antigenic specific T suppressor (Ts) cells that inhibit CD4 and CD8 T cell effector function both in vitro and in vivo. ILT3-Fc–induced CD8+ Ts cells express high amounts of BCL6 that are crucial to their function. Knockdown of BCL6 from unprimed human T cells prevents their differentiation into Ts cells, whereas ex vivo overexpression of BCL6 converts CD8+ T cells into Ts cells. NOD/SCID mice transplanted with human pancreatic islets and humanized by injection of human PBMCs tolerate the graft and develop BCL6high CD8+ Ts cells when treated with ILT3-Fc before or after the onset of rejection. This indicates that ILT3-Fc acts through BCL6 and is a potent immunosuppressive agent for reversing the onset of allo- or possibly autoimmune attacks against pancreatic islets.

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Section: Discussionsupporting

confidence: 82%

BCL6 Is Required for Differentiation of Ig-Like Transcript 3-Fc–Induced CD8+ T Suppressor Cells

Chang

Vlad²,

D’Agati³

et al. 2010

The Journal of Immunology

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“…This might be, at least in part, because of the heterogeneity and complexity of regulatory CD8 T cell subsets, each of which might be involved in different aspects of immune responses (11). Suzuki and colleagues (5) demonstrated that naturally occurring CD8 Tregs expressed CD122, although it was widely accepted that CD122 is a marker of memory CD8 T cells.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to CD122 + CD8 T cells, various subsets of CD8 T cells were reported to have regulatory activity (9)(10)(11). In earlier studies, it was shown that injecting cyclophosphamide (CP) in mice enhanced immune responses that were suppressed by complementing T cells from nontreated mice (10).…”

mentioning

confidence: 99%

Naturally Occurring PD-1+ Memory Phenotype CD8 T Cells Belong to Nonconventional CD8 T Cells and Are Cyclophosphamide-Sensitive Regulatory T Cells

Sakuraba

Shibata

Iwamoto

et al. 2013

The Journal of Immunology

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CD8 T cells expressing memory markers exist in naive mice and are thought to be of heterogeneous origin. It was recently reported that among such memory-phenotype (MP) CD8 T cells in naive mice, those expressing programmed death-1 (PD-1) had immune regulatory activity, but their origin and relationship with other regulatory CD8 T cell subsets remain unclear. In the current study, we examined detailed characteristics and functions of PD-1+ MP CD8 T cells in naive mice. Their expression pattern of surface molecules resembled that of exhausted CD8 T cells seen in chronic viral infection. However, PD-1+ MP CD8 T cells were detected from neonatal periods, even in the thymus; thus, they are naturally occurring. By analyzing bone marrow chimera mice in which β2-microglobulin–deficient mice were used as the recipients, it was revealed that PD-1+ MP CD8 T cells were positively selected by hematopoietic cells, indicating that they belong to nonconventional CD8 T cells. However, in contrast to majority of MP CD8 T cells, PD-1+ MP CD8 T cells were IL-15 independent. PD-1+ MP CD8 T cells showed the fastest cell cycling among various T cell subsets in naive mice, which was consistent with the highest sensitivity to cyclophosphamide (CP) treatment. Importantly, PD-1+ MP CD8 T cells were able to suppress delayed-type hypersensitivity response that was augmented by CP treatment. Taken together, our data indicate that the naturally occurring PD-1+ MP CD8 T cells in naive mice are a unique subset of nonconventional CD8 T cells and represent the CP-sensitive suppressor CD8 T cells.

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“…These CD8 ? 'Tregs' function in EAE in rodents, the NZB/NZW mouse model of SLE, NOD mouse diabetes, and murine models of myasthenia gravis and rheumatoid arthritis and have been demonstrated in inflammatory bowel disease and multiple sclerosis in humans [90][91][92]. These CD8 ?…”

Section: Self-tolerance To Mrbc Maintained By Regulatory T Cellsmentioning

confidence: 96%

“…Tregs (reviewed in [60,[87][88][89]); however, there are increasing numbers of modern reports of CD8 ? 'Tregs' (reviewed in [90][91][92]). These CD8 ?…”

Section: Self-tolerance To Mrbc Maintained By Regulatory T Cellsmentioning

confidence: 99%

Regulatory T cells essential to prevent the loss of self-tolerance in murine models of erythrocyte-specific autoantibody responses

Calkins

2011

Immunol Res

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The spontaneous appearance of anti-erythrocyte autoantibodies resulting in autoimmune hemolytic anemia described in NZB mice more than 40 years ago provided a model for the study of mechanisms behind the loss of self-tolerance. We developed an in vitro model of this anti-MRBC response in which CD8(+) suppressor T cells were shown to be a controlling element. CD8(+) T cells from young NZB mice co-cultured with spleen cells from old, actively autoimmune NZB mice suppressed the anti-MRBC responses of the old mice. Eliminating the CD8(+) cells from young NZB spleen cells or even from non-autoimmune BALB/c spleen cells prior to culture removed the controlling influence of these CD8(+) cells and allowed the development of anti-MRBC-secreting cells. This review will consider the role of the CD8(+) suppressive cells in the anti-self-erythrocyte model in light of insights provided by current 'regulatory T cell' literature.

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CD8+ Tregs in lupus, autoimmunity, and beyond

Cited by 116 publications

References 151 publications

BCL6 Is Required for Differentiation of Ig-Like Transcript 3-Fc–Induced CD8+ T Suppressor Cells

BCL6 Is Required for Differentiation of Ig-Like Transcript 3-Fc–Induced CD8+ T Suppressor Cells

Naturally Occurring PD-1+ Memory Phenotype CD8 T Cells Belong to Nonconventional CD8 T Cells and Are Cyclophosphamide-Sensitive Regulatory T Cells

Regulatory T cells essential to prevent the loss of self-tolerance in murine models of erythrocyte-specific autoantibody responses

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