Alloantigen-specific type 1 regulatory T cells suppress through CTLA-4 and PD-1 pathways and persist long-term in patients

Chen, Pauline Ping; Cepika, Alma-Martina; Agarwal-Hashmi, Rajni; Saini, Gopin; Uyeda, Molly Javier; Louis, David M.; Cieniewicz, Brandon; Narula, Mansi; Amaya, Laura; Harre, Nicholas; Xu, Liwen; Thomas, Benjamin; Ji, Xuhuai; Shiraz, Parveen; Tate, Keri; Margittai, Dana; Bhatia, Neehar; Meyer, Everett; Bertaina, Alice; Davis, Mark M.; Bacchetta, Rosa; Roncarolo, Maria Grazia

doi:10.1126/scitranslmed.abf5264

Cited by 43 publications

(82 citation statements)

References 78 publications

(144 reference statements)

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“…Ovalbumin-specific Tr1 cell clones were administrated to Chron's disease patients with no side effects, but limited clinical efficacy [84]. Our group developed a DC-10-based protocol to generate in vitro Ag-specific Tr1 cells [28] that have been used to prevent graftversus host disease after bone marrow transplantation [85]. Thus far, DC-10 pulsed with Ags have been used to differentiate allergen-specific Tr1 cells form allergic patients [86].…”

Section: Discussionmentioning

confidence: 99%

Alteration of interleukin-10-producing Type 1 regulatory cells in autoimmune diseases

Gregori

Amodio

Passerini

et al. 2022

Current Opinion in Hematology

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Purpose of reviewThis review highlights findings describing the role of interleukin (IL)-10-producing Type 1 regulatory T (Tr1) cells in controlling autoimmune diseases and possible approaches to restore their function and number. Recent findingsReduced frequency and/or function of cell subsets playing a role in Tr1 cell induction (e.g., DC-10 and Bregs), was found in patients with autoimmunity and may impact on Tr1 cell frequency.

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Section: Discussionmentioning

confidence: 99%

Alteration of interleukin-10-producing Type 1 regulatory cells in autoimmune diseases

Gregori

Amodio

Passerini

et al. 2022

Current Opinion in Hematology

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“…This was also accompanied by a decreased frequency of PbTII ΔSting cells producing granzyme (Gzm) B and perforin, relative to PbTII WT cells (Figure S6A-C). The expression of these cytotoxic molecules has previously been associated with both mouse and human Tr1 cells (Chen et al, 2021; Hidalgo et al, 2008). However, differences in Tr1 cells defined by LAG3 and CD49b expression were less consistent between PbTII ΔSting and PbTII WT cells (Figure 5D).…”

Section: Resultsmentioning

confidence: 99%

STING activation promotes autologous type I interferon-dependent development of type 1 regulatory T cells during malaria

Wang

Rivera

Edwards

et al. 2022

Preprint

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The development of highly effective malaria vaccines and improving drug treatment protocols to boost anti-parasitic immunity is critical for malaria elimination. However, these efforts are hampered by parasite-specific immunoregulatory networks that are rapidly established following exposure to malaria parasites. Here, we identify stimulator of interferon genes (STING) as a critical mediator of type I interferon production by CD4+ T cells during blood-stage Plasmodium falciparum infection. STING activation by cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) stimulated IFNB gene transcription that promoted development of IL-10 and IFNγ co-producing CD4+ T (type I regulatory; Tr1) cells. CD4+ T cell sensitivity to STING phosphorylation increased in healthy volunteers following P. falciparum infection, particularly in Tr1 cells. Finally, we found the JAK1/2 inhibitor ruxolitinib modulated this innate signalling axis in CD4+ T cells to increase parasite-specific Th1 and diminish Tr1 cell responses. These findings identify STING as a critical mediator of Tr1 cell development during malaria.

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“…Tr1 cells can also inhibit the activation of effector cells via binding immune checkpoint molecules such as PD-1 and CTLA-4. Chen et al ( 154 ) demonstrated that blocking CTLA-4 or PD-1/ programmed cell death ligand 1 almost completely abolished human Tr1 cell-mediated inhibition of effector T cell proliferation. Akdis et al ( 74 ) also reported that human Tr1 cells suppressed the production of IL-13 from Der p 1 or Bet v 1-specific Th2 by down-modulation of antigen-presenting cells through expressions of CTLA-4 and PD-1 on Tr1 cells.…”

Section: Immunosuppressive Roles Of Tr1 Cellsmentioning

confidence: 96%

Roles of type 1 regulatory T (Tr1) cells in allergen-specific immunotherapy

et al. 2022

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Allergen-specific immunotherapy (AIT) is the only causative treatment for allergic diseases by modification of the immune response to allergens. A key feature of AIT is to induce immunotolerance to allergens by generating antigen-specific regulatory T (Treg) cells in allergic patients. Type 1 regulatory T (Tr1) cells and forkhead box protein 3 (Foxp3)-expressing Treg cells are well known among Treg cell subsets. Foxp3 was identified as a master transcription factor of Treg cells, and its expression is necessary for their suppressive activity. In contrast to Foxp3+ Treg cells, the master transcription factor of Tr1 cells has not been elucidated. Nevertheless, Tr1 cells are generally considered as a distinct subset of Treg cells induced in the periphery during antigen exposure in tolerogenic conditions and can produce large amounts of anti-inflammatory cytokines such as interleukin-10 and transforming growth factor-β, followed by down-regulation of the function of effector immune cells independently of Foxp3 expression. Since the discovery of Tr1 cells more than 20 years ago, research on Tr1 cells has expanded our understanding of the mechanism of AIT. Although the direct precursors and true identity of these cells continues to be disputed, we and others have demonstrated that Tr1 cells are induced in the periphery by AIT, and the induced cells are re-activated by antigens, followed by suppression of allergic symptoms. In this review, we discuss the immune mechanisms for the induction of Tr1 cells by AIT and the immune-suppressive roles of Tr1 cells in AIT.

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Alloantigen-specific type 1 regulatory T cells suppress through CTLA-4 and PD-1 pathways and persist long-term in patients

Abstract: Type 1 regulatory T cells suppress alloreactive immune cells after adoptive transfer in a CTLA-4 and PD-1–mediated manner.

Cited by 43 publications

References 78 publications

Alteration of interleukin-10-producing Type 1 regulatory cells in autoimmune diseases

Alteration of interleukin-10-producing Type 1 regulatory cells in autoimmune diseases

STING activation promotes autologous type I interferon-dependent development of type 1 regulatory T cells during malaria

Roles of type 1 regulatory T (Tr1) cells in allergen-specific immunotherapy

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