CD4+CD25+CD127-Foxp3+ and CD8+CD28- Tregs in Renal Transplant Recipients: Phenotypic Patterns, Association With Immunosuppressive Drugs, and Interaction With Effector CD8+ T Cells and CD19+IL-10+ Bregs

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2021 Aug 2

PMID 34335631

Citations 7

Authors

Mostafa G Aly

Eman H Ibrahim

Hristos Karakizlis

Rolf Weimer

Gerhard Opelz

Christian Morath

Martin Zeier

Naruemol Ekpoom

Volker Daniel

Affiliations

Soon will be listed here.

Abstract

Introduction: Gaps still exist regarding knowledge on regulatory cells in transplant recipients. We studied the phenotypic patterns of CD4+, CD8+CD28- Tregs, and CD19+IL-10+ Bregs in the blood of healthy controls (HC), end-stage kidney disease patients (ESKD), early and late stable renal transplant recipients (Tx), and transplant recipients with steroid-treated acute cellular rejection 1 week-3 months after successful treatment. We also investigated the relationship between immunosuppressive drugs and the aforementioned regulatory cells in transplant recipients.

Methods: We recruited 32 HC, 83 ESKD, 51 early Tx, 95 late Tx, and 9 transplant patients with a recent steroid-treated acute cellular rejection. Besides CD19+IL-10+ Bregs, we analyzed absolute and relative frequencies of CD4+CD25+CD127-Foxp3+ Tregs and CD8+CD28- Tregs and their expression of IL-10, TGF-ß, IFN-g, and Helios.

Results: We found a negative correlation between absolute CD4+CD25+CD127-Foxp3+ Treg and relative CD19+IL-10+ Breg frequencies in early Tx recipients (r=-0.433, =0.015, n=31). In that group, absolute CD4+CD25+CD127-Foxp3+ Tregs were negatively associated with steroid dose and tacrolimus trough levels (r=-0.377, = 0.021, n=37; r=-0.43, =0.033, n=25, respectively), opposite to IL-10+ Bregs, whose frequency apparently was not negatively affected by potent immunosuppression early posttransplant. We found also lower CD4+CD25+CD127-Foxp3+ Tregs in patients treated with basiliximab or rATG as compared with ESKD patients (=0.001 and 0.001, respectively). No difference in absolute IL-10+ Bregs could be detected among these 3 patient groups. Early Tx recipients showed lower CD4+CD25+CD127-Foxp3+ Tregs within 3 months of antibody induction than after 3 months ( = 0.034), whereas IL-10+ Bregs showed higher relative counts during the first 3 months post antibody induction than after 3 months ( = 0.022). Our findings suggest that IL-10+ Bregs decrease with time posttransplantation independent of the effect of antibody induction and dose of other immunosuppressive drugs.

Conclusion: These findings suggest that CD19+IL-10+ Bregs and CD4+CD25+CD127-Foxp3+ Tregs behave in opposite ways during the early posttransplant period, possibly due to a predominant negative impact of high doses of immunosuppressants on Tregs. CD19+IL-10+Bregs do not seem to be suppressed by antibody induction and early potent immunosuppression with chemical drugs.

Citing Articles

Impact of immunosuppressants on tumor pulmonary metastasis: new insight into transplantation for hepatocellular carcinoma.

Chen J, Li H, Zhuo J, Lin Z, Hu Z, He C Cancer Biol Med. 2024; 21(11.

PMID: 39718153 PMC: 11667780. DOI: 10.20892/j.issn.2095-3941.2024.0267.

Regulatory T cells in immune checkpoint blockade antitumor therapy.

Zhang A, Fan T, Liu Y, Yu G, Li C, Jiang Z Mol Cancer. 2024; 23(1):251.

PMID: 39516941 PMC: 11545879. DOI: 10.1186/s12943-024-02156-y.

Evaluation of Regulatory B Cell Subpopulations CD24++CD38++, CD24++CD27+, Plasmablasts and Their Correlation with T Regs CD3+CD4+CD25+FOXP3+ in Dialysis Patients and Early Post-Transplant Rejection-Free Kidney Recipients.

Fouza A, Fylaktou A, Tagkouta A, Daoudaki M, Vagiotas L, Kasimatis E J Clin Med. 2024; 13(11).

PMID: 38892795 PMC: 11173263. DOI: 10.3390/jcm13113080.

Treg in inborn errors of immunity: gaps, knowns and future perspectives.

Kennedy-Batalla R, Acevedo D, Luo Y, Esteve-Sole A, Vlagea A, Correa-Rocha R Front Immunol. 2024; 14:1278759.

PMID: 38259469 PMC: 10800401. DOI: 10.3389/fimmu.2023.1278759.

Regulatory T cells in skin regeneration and wound healing.

Knoedler S, Knoedler L, Kauke-Navarro M, Rinkevich Y, Hundeshagen G, Harhaus L Mil Med Res. 2023; 10(1):49.

PMID: 37867188 PMC: 10591349. DOI: 10.1186/s40779-023-00484-6.

References

Posnett D, Edinger J, Manavalan J, Irwin C, Marodon G . Differentiation of human CD8 T cells: implications for in vivo persistence of CD8+ CD28- cytotoxic effector clones. Int Immunol. 1999; 11(2):229-41. DOI: 10.1093/intimm/11.2.229. View

Daniel V, Wang H, Sadeghi M, Opelz G . Interferon-gamma producing regulatory T cells as a diagnostic and therapeutic tool in organ transplantation. Int Rev Immunol. 2013; 33(3):195-211. DOI: 10.3109/08830185.2013.845181. View

Sakaguchi S, Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T . Regulatory T cells: how do they suppress immune responses?. Int Immunol. 2009; 21(10):1105-11. DOI: 10.1093/intimm/dxp095. View

Campbell D, Koch M . Phenotypical and functional specialization of FOXP3+ regulatory T cells. Nat Rev Immunol. 2011; 11(2):119-30. PMC: 3289970. DOI: 10.1038/nri2916. View

Cortesini R, LeMaoult J, Ciubotariu R, Cortesini N . CD8+CD28- T suppressor cells and the induction of antigen-specific, antigen-presenting cell-mediated suppression of Th reactivity. Immunol Rev. 2001; 182:201-6. DOI: 10.1034/j.1600-065x.2001.1820116.x. View

Floess S, Freyer J, Siewert C, Baron U, Olek S, Polansky J . Epigenetic control of the foxp3 locus in regulatory T cells. PLoS Biol. 2007; 5(2):e38. PMC: 1783672. DOI: 10.1371/journal.pbio.0050038. View

Filaci G, Fravega M, Negrini S, Procopio F, Fenoglio D, Rizzi M . Nonantigen specific CD8+ T suppressor lymphocytes originate from CD8+CD28- T cells and inhibit both T-cell proliferation and CTL function. Hum Immunol. 2004; 65(2):142-56. DOI: 10.1016/j.humimm.2003.12.001. View

Gottschalk R, Corse E, Allison J . Expression of Helios in peripherally induced Foxp3+ regulatory T cells. J Immunol. 2011; 188(3):976-80. DOI: 10.4049/jimmunol.1102964. View

Abbas A, Benoist C, Bluestone J, Campbell D, Ghosh S, Hori S . Regulatory T cells: recommendations to simplify the nomenclature. Nat Immunol. 2013; 14(4):307-8. DOI: 10.1038/ni.2554. View

10.

Yang N, Li Z, Jiao Z, Gu P, Zhou Y, Lu L . A Trichosanthin-derived peptide suppresses type 1 immune responses by TLR2-dependent activation of CD8(+)CD28(-) Tregs. Clin Immunol. 2014; 153(2):277-87. DOI: 10.1016/j.clim.2014.05.005. View

11.

Collison L, Workman C, Kuo T, Boyd K, Wang Y, Vignali K . The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature. 2007; 450(7169):566-9. DOI: 10.1038/nature06306. View

12.

Karczewski J, Karczewski M, Wiktorowicz K . Possible defect of T suppressor cell subpopulation in patients with kidney acute rejection. Transplant Proc. 2010; 42(10):4538-9. DOI: 10.1016/j.transproceed.2010.09.174. View

13.

Feuerer M, Hill J, Mathis D, Benoist C . Foxp3+ regulatory T cells: differentiation, specification, subphenotypes. Nat Immunol. 2009; 10(7):689-95. DOI: 10.1038/ni.1760. View

14.

Rubtsov Y, Rasmussen J, Chi E, Fontenot J, Castelli L, Ye X . Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces. Immunity. 2008; 28(4):546-58. DOI: 10.1016/j.immuni.2008.02.017. View

15.

Trentin L, Zambello R, Faggian G, Livi U, Thiene G, Gasparotto G . Phenotypic and functional characterization of cytotoxic cells derived from endomyocardial biopsies in human cardiac allografts. Cell Immunol. 1992; 141(2):332-41. DOI: 10.1016/0008-8749(92)90152-f. View

16.

Turner J, Stephen-Victor E, Wang S, Noval Rivas M, Abdel-Gadir A, Harb H . Regulatory T Cell-Derived TGF-β1 Controls Multiple Checkpoints Governing Allergy and Autoimmunity. Immunity. 2020; 53(6):1202-1214.e6. PMC: 7744401. DOI: 10.1016/j.immuni.2020.10.002. View

17.

Vuddamalay Y, van Meerwijk J . CD28 and CD28CD8 Regulatory T Cells: Of Mice and Men. Front Immunol. 2017; 8:31. PMC: 5256148. DOI: 10.3389/fimmu.2017.00031. View

18.

Valdez-Ortiz R, Bestard O, Llaudo I, Franquesa M, Cerezo G, Torras J . Induction of suppressive allogeneic regulatory T cells via rabbit antithymocyte polyclonal globulin during homeostatic proliferation in rat kidney transplantation. Transpl Int. 2014; 28(1):108-19. DOI: 10.1111/tri.12448. View

19.

Fenoglio D, Ferrera F, Fravega M, Balestra P, Battaglia F, Proietti M . Advancements on phenotypic and functional characterization of non-antigen-specific CD8+CD28- regulatory T cells. Hum Immunol. 2008; 69(11):745-50. DOI: 10.1016/j.humimm.2008.08.282. View

20.

Lu Y, Liu F, Li C, Chen Y, Weng D, Chen J . IL-10-Producing B Cells Suppress Effector T Cells Activation and Promote Regulatory T Cells in Crystalline Silica-Induced Inflammatory Response In Vitro. Mediators Inflamm. 2017; 2017:8415094. PMC: 5558645. DOI: 10.1155/2017/8415094. View