Transplantation Survival Is Maintained by Granzyme B+ Regulatory Cells and Adaptive Regulatory T Cells

Gondek, David; Devries, Victor; Nowak, Elizabeth C.; Lu, Li-Fan; Bennett, Kathryn A.; Scott, Zachary; Noelle, Randolph J.

doi:10.4049/jimmunol.181.7.4752

Cited by 87 publications

(59 citation statements)

References 70 publications

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“…Importantly, granzyme B is also expressed in Tregs and plays a role in their suppressive function by allowing them to lyse CD4 + T cells [97]. Consistent with this observation, expression of granzyme B in Foxp3 + cells was necessary for the induction of skin allograft tolerance in mice [98], a reminder that effector pathways can have opposite consequences depending on the cells in which they are expressed.…”

Section: Effector Phase Of the Alloimmune Response: T Cells Go To Thesupporting

confidence: 65%

Cellular Mechanisms of Adaptive Immunity

Alegre

2014

Textbook of Organ Transplantation

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Section: Effector Phase Of the Alloimmune Response: T Cells Go To Thesupporting

confidence: 65%

Cellular Mechanisms of Adaptive Immunity

Alegre

2014

Textbook of Organ Transplantation

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“…35 Gondek et al later validated their in vitro findings in a skin allograft model by showing that hosts reconstituted with granzyme B-deficient T reg cells were unable to establish long-term tolerance to skin allografts. 36 This presents a dichotomy in the mechanisms used by alloactivated T reg cells to suppress effector immune responses, even though allogeneic T-cell activation is a shared feature of all of these models. In the tumor model, the perforin/granzyme pathway is a nonredundant component of T reg -cell function, although others have shown that additional molecules, such as CTLA-4 and GITR, also play important roles.…”

Section: Discussionmentioning

confidence: 99%

Granzyme B is not required for regulatory T cell–mediated suppression of graft-versus-host disease

Cai

Cao

Hassan

et al. 2010

Blood

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Regulatory T (T reg ) cells can suppress a wide variety of immune responses, including antitumor and alloimmune responses.The mechanisms by which T reg cells mediate their suppressive effects depend on the context of their activation. We previously reported that granzyme B is important for T reg cell-mediated suppression of antitumor immune responses. We therefore hypothesized that granzyme B may likewise be important for suppression of graft-versus-host disease (GVHD). We found that allogeneic mismatch induces the expression of granzyme B in mixed lymphocyte reactions and in a model of graft-versus-host disease (GVHD). However, wild-type and granzyme B-deficient T reg cells were equally able to suppress effector T (T eff ) cell proliferation driven by multiple stimuli, including allogeneic antigen-presenting cells. Surprisingly, adoptive transfer of granzyme B-deficient T reg cells prevented GVHD lethality, suppressed serum cytokine production in vivo, and prevented target organ damage. These data contrast strikingly with our previous study, which demonstrated that granzyme B plays a nonredundant role in T reg cell-mediated suppression of antitumor responses. Taken together, these findings suggest that targeting specific T reg cell-suppressive mechanisms, such as granzyme B, may be therapeutically beneficial for segregating GVHD and graft-versus-tumor immune responses. (Blood. 2010;115: 1669-1677) IntroductionCD4 ϩ Foxp3 ϩ regulatory T (T reg ) cells play an indispensable role in maintaining peripheral tolerance to self-antigens by suppressing effector immune responses. Mice or humans with a deficiency of T reg cells, induced by antibody-mediated 1,2 or toxin-mediated 3,4 depletion or by mutations 5 and deletions 6,7 of the lineage specification factor Foxp3, manifest severe autoimmune disease. In addition to preventing autoimmunity, T reg cells can also suppress immune responses generated against tumor cells, 8,9 alloantigens, 10 allergens, [11][12][13] and microbial antigens. 14,15 Several mechanisms have been proposed to explain how T reg cellmediated suppression of effector immune responses occurs. In certain model systems, T reg -cell secretion of anti-inflammatory cytokines, such as transforming growth factor-␤ and interleukin-10 (IL-10), has been shown to be required for suppressive function. [16][17][18] In other experimental settings, contact-dependent mechanisms, such as interactions between CTLA-4 on T reg cells and CD80/CD86 on antigen-presenting cells (APCs), have also been reported. [19][20][21] Because of the variety of animal models, in vitro activation methods, and readouts for suppression, rigorously defining nonredundant T reg -suppressive mechanisms has been challenging and controversial. It is probable that T reg cells use multiple mechanisms depending on the context in which they are activated in vivo. 22 Our group previously demonstrated that human regulatory T cells can use the perforin/granzyme pathway to suppress effector T (T eff )-cell proliferation and kill autologous immune cells. ...

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“…Others have shown that GzmB can be produced by human (51) and mouse (52,53) Treg cells and that via expression of this molecule, murine Treg cells can suppress the functions of T cells (54,55), NK cells (55), and B cells (53) in vivo. Consistent with these reports, we also detected GzmB production by splenic Treg cells during PbA infection (Supplemental Fig.…”

Section: Discussionmentioning

confidence: 99%

Granzyme B Expression by CD8+ T Cells Is Required for the Development of Experimental Cerebral Malaria

Haque

Best

Unosson

et al. 2011

The Journal of Immunology

171

210

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Parasite burden predicts disease severity in malaria and risk of death in cerebral malaria patients. In murine experimental cerebral malaria (ECM), parasite burden and CD8+ T cells promote disease by mechanisms that are not fully understood. We found that the majority of brain-recruited CD8+ T cells expressed granzyme B (GzmB). Furthermore, gzmB−/− mice harbored reduced parasite numbers in the brain as a consequence of enhanced antiparasitic CD4+ T cell responses and were protected from ECM. We showed in these ECM-resistant mice that adoptively transferred, Ag-specific CD8+ T cells migrated to the brain, but did not induce ECM until a critical Ag threshold was reached. ECM induction was exquisitely dependent on Ag-specific CD8+ T cell-derived perforin and GzmB, but not IFN-γ. In wild-type mice, full activation of brain-recruited CD8+ T cells also depended on a critical number of parasites in this tissue, which in turn, was sustained by these tissue-recruited cells. Thus, an interdependent relationship between parasite burden and CD8+ T cells dictates the onset of perforin/GzmB-mediated ECM.

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Transplantation Survival Is Maintained by Granzyme B+ Regulatory Cells and Adaptive Regulatory T Cells

Cited by 87 publications

References 70 publications

Cellular Mechanisms of Adaptive Immunity

Cellular Mechanisms of Adaptive Immunity

Granzyme B is not required for regulatory T cell–mediated suppression of graft-versus-host disease

Granzyme B Expression by CD8+ T Cells Is Required for the Development of Experimental Cerebral Malaria

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