Future prospects for CD8+ regulatory T cells in immune tolerance

Flippe, Léa; Bézie, Séverine; Anegón, Ignacio; Guillonneau, Carole

doi:10.1111/imr.12812

Cited by 74 publications

(84 citation statements)

References 215 publications

(385 reference statements)

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“…We obtained more than an 100fold expansion of CD8 + Tregs with either IL-34-differentiated macrophages (named IL-34-Tregs) or untreated macrophages (named Tregs) ( Figure 5E). After expansion, IL-34-Tregs were highly enriched in FOXP3 + cells, expressed higher levels of surface markers commonly related to CD4 + and CD8 + Tregs, such as GITR and PD-1, and cytokines such as TGFβ, IFNγ, and IL-34 that we have demonstrated as being mediators of CD8 + Treg-suppressive activity (23,24) (Figure 5F and Supplementary Figure 4B).…”

Section: Il-34 Induces More Efficiently Than Csf-1 Foxp3 + Tregs Whmentioning

confidence: 87%

“…The synergy between IL-34 and anti-CD45RC mAb also suggests that in vivo IL-34 efficacy may be limited by Teff cells. Although the synergistic capacity of CD4 + and CD8 + Tregs is not yet clear, both subsets could show complementary effects and it could be beneficial to administer them together to patients (24). IL-34 could also be used in vivo together with Treg cell therapy to promote the persistence and the function of the induced Tregs, as is done with low-dose IL-2 or rapamycin (52,53), by enrichment of the environment with tolerogenic macrophages and by direct action on Tregs.…”

Section: Discussionmentioning

confidence: 99%

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IL-34 Actions on FOXP3+ Tregs and CD14+ Monocytes Control Human Graft Rejection

et al. 2020

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Cytokines are major players regulating immune responses toward inflammatory and tolerogenic results. In organ and bone marrow transplantation, new reagents are needed to inhibit tissue destructive mechanisms and eventually induce immune tolerance without overall immunosuppression. IL-34 is a cytokine with no significant homology with any other cytokine but that acts preferentially through CSF-1R, as CSF-1 does, and through PTPζ and CD138. Although IL-34 and CSF-1 share actions, a detailed analysis of their effects on immune cells needs further research. We previously showed that both CD4 + and CD8 + FOXP3 + Tregs suppress effector T cells through the production of IL-34, but not CSF-1, and that this action was mediated through antigen-presenting cells. We showed here by single-cell RNAseq and cytofluorimetry that different subsets of human monocytes expressed different levels of CSF-1R, CD138, and PTPζ and that both CD4 + and CD8 + FOXP3 + Tregs expressed higher levels of CSF-1R than conventional T cells. The effects of IL-34 differed in the survival of these different subpopulations of monocytes and RNAseq analysis showed several genes differentially expressed between IL-34, CSF-1, M0, M1, and also M2 macrophages. Acute graftvs.-host disease (aGVHD) in immunodeficient NSG mice injected with human PBMCs was decreased when treated with IL-34 in combination with an anti-CD45RC mAb that depleted conventional T cells. When IL-34-differentiated monocytes were used to expand Tregs in vitro, both CD4 + and CD8 + FOXP3 + Tregs were highly enriched and this effect was superior to the one obtained with CSF-1. Human CD8 + Tregs expanded in vitro with IL-34-differentiated allogeneic monocytes suppressed human immune responses in an NSG mouse aGVHD model humanized with hPBMCs. Overall, we showed that IL-34 induced the differentiation of human monocytes with a particular transcriptional profile and these cells favored the development of potent suppressor FOXP3 + Tregs.

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Section: Il-34 Induces More Efficiently Than Csf-1 Foxp3 + Tregs Whmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

IL-34 Actions on FOXP3+ Tregs and CD14+ Monocytes Control Human Graft Rejection

et al. 2020

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“…Recent interest in CD8+ Treg lead to their phenotypic and functional characterization [ 65 , 66 , 67 ]. CD8+ Treg have shown to play an important role in immune homeostasis, including inhibition of B-cell proliferation and differentiation of B cells into immunoglobulin-secreting plasmablasts [ 67 , 68 ].…”

Section: Discussionmentioning

confidence: 99%

SARS-CoV-2-Associated T-Cell Responses in the Presence of Humoral Immunodeficiency

Gupta

Narsai

et al. 2021

Int Arch Allergy Immunol

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We report perhaps the most comprehensive study of subsets of CD4+ and CD8+ and subsets of B cells in a mild symptomatic SARS-CoV-2+ immunocompetent patient and a common variable immunodeficiency disease (CVID) patient who had normal absolute lymphocyte counts and remained negative for SARS-CoV-2 IgG antibodies. Naïve (TN), central memory (TCM), effector memory (TEM), and terminally differentiated effector memory (TEMRA) subsets of CD4+ and CD8+ T cells, subsets of T follicular helper cells (cTFH, TFH1, TFH2, TFH17, TFH1/TFH17, and TFR), CD4 Treg, CD8 Treg, mature B cells, transitional B cells, marginal zone B cells, germinal center (GC) B cells, CD21low B cells, antibody-secreting cells (plasmablasts), and Breg cells were examined in patients and age-matched controls with appropriate monoclonal antibodies and isotype controls using multicolor flow cytometry. Different patterns of abnormalities (often contrasting) were observed in the subsets of CD4+ T, CD8+ T, B-cell subsets, and regulatory lymphocytes among the immunocompetent patient and CVID patient as compared to corresponding healthy controls. Furthermore, when data were analyzed between the 2 patients, the immunocompetent patient demonstrated greater changes in various subsets as compared to the CVID patient. These data demonstrate different immunological responses to SARS-CoV-2 infection in an immunocompetent patient and the CVID patient. A marked decrease in GC B cells and plasmablasts may be responsible for failure to make SARS-CoV-2 antibodies. The lack of SARS-CoV-2 antibodies with mild clinical disease suggests an important role of T-cell response in defense against SARS-CoV-2 infection.

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“…It is well known that CD8 + and CD4 + Tregs recognize their cognate antigens presented by major histocompatibility complex class I molecule (MHC-I) or MHC-II on relevant cell types, respectively. Hence, CD8 + Tregs will display their suppressive activities on virtually all cells, whereas CD4 + Tregs' suppressive abilities will occur only on cells expressing MHC-II molecules [31]. Based on these, we think it very important to investigate the functional mechanisms of CD8 + Tregs and to exploit the CD8 + Treg-cell therapy.…”

Section: Discussionmentioning

confidence: 99%

CD8+ Tregs Ameliorate Inflammatory Reactions in a Murine Model of Allergic Rhinitis

Lin

Dai

Wei

et al. 2021

Preprint

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Background CD8+CD25+fork-head box transcription factor (Foxp3)+ regulatory T cells (CD8+ Tregs) play a role in immune tolerance. However, the role of these cells in allergic rhinitis (AR) has not been elucidated. The study aimed to evaluate influences of CD8+ Tregs on inflammatory conditions in a murine model of AR. Methods A murine model of AR was established. CD8+ Tregs were isolated from mice nasal mucosa and cultured in vitro. We examined interleukin (IL)-10 and transforming growth factor (TGF)-β in cell cultures. Then, we administered CD8+ Tregs into mice nasal mucosal cultures, and examined eosinophil cation protein (ECP), IL-4, IL-5 and IL-13 in these cultures. Finally, we adoptively transferred CD8+ Tregs into mice models, and evaluated percentages of CD8+ Tregs, numbers of sneezing and nasal rubbing, and counts of eosinophils and contents of ECP, IL-4, IL-5, IL-13, IL-10 and TGF-β in nasal lavage fluid (NLF) in mice. Results The percentage of CD8+ Tregs from AR mice was reduced. IL-10 and TGF-β were increased in cell cultures from AR mice. ECP, IL-4, IL-5 and IL-13 were decreased after the AR mice CD8+ Tregs administration in mucosal cultures. However, their contents were not changed after normal CD8+ Tregs treatment. Additionally, the adoptive transfer of AR CD8+ Tregs enhanced the percentage of CD8+ Tregs and levels of IL-10 and TGF-β in NLF, reduced numbers of sneezing and nasal rubbing, and counts of eosinophils and concentrations of ECP, IL-4, IL-5 and IL-13 in NLF. However, normal CD8+ Tregs could not change above parameters. Conclusion These findings show that CD8+ Tregs may inhibit inflammatory responses in the AR condition.

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Future prospects for CD8⁺ regulatory T cells in immune tolerance

Cited by 74 publications

References 215 publications

IL-34 Actions on FOXP3+ Tregs and CD14+ Monocytes Control Human Graft Rejection

IL-34 Actions on FOXP3+ Tregs and CD14+ Monocytes Control Human Graft Rejection

SARS-CoV-2-Associated T-Cell Responses in the Presence of Humoral Immunodeficiency

CD8+ Tregs Ameliorate Inflammatory Reactions in a Murine Model of Allergic Rhinitis

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