IFNγ-induction of T1-like Regulatory T Cells Controls Antiviral Responses

Overview

Journal Nat Immunol

Date 2023 Mar 17

PMID 36928412

Authors

Angela M Gocher-Demske

Jian Cui

Andrea L Szymczak-Workman

Kate M Vignali

Julianna N Latini

Gwen P Pieklo

Jesse C Kimball

Lyndsay Avery

Ellyse M Cipolla

Brydie R Huckestein

Lee Hedden

Marlies Meisel

John F Alcorn

Lawrence P Kane

Creg J Workman

Dario A A Vignali

Affiliations

Soon will be listed here.

Abstract

Regulatory T (T) cells are an immunosuppressive population that are required to maintain peripheral tolerance and prevent tissue damage from immunopathology, via anti-inflammatory cytokines, inhibitor receptors and metabolic disruption. Here we show that T cells acquire an effector-like state, yet remain stable and functional, when exposed to interferon gamma (IFNγ) during infection with lymphocytic choriomeningitis and influenza A virus. T cell-restricted deletion of the IFNγ receptor (encoded by Ifngr1), but not the interleukin 12 (IL12) receptor (encoded by Il12rb2), prevented T1-like polarization (decreased expression of T-bet, CXC motif chemokine receptor 3 and IFNγ) and promoted T2-like polarization (increased expression of GATA-3, CCR4 and IL4). T1-like T cells limited CD8 T cell effector function, proliferation and memory formation during acute and chronic infection. These findings provide fundamental insights into how T cells sense inflammatory cues from the environment (such as IFNγ) during viral infection to provide guidance to the effector immune response. This regulatory circuit prevents prolonged immunoinflammatory responses and shapes the quality and quantity of the memory T cell response.

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References

Veiga-Parga T, Sehrawat S, Rouse B . Role of regulatory T cells during virus infection. Immunol Rev. 2013; 255(1):182-96. PMC: 3748387. DOI: 10.1111/imr.12085. View

Punkosdy G, Blain M, Glass D, Lozano M, OMara L, Dudley J . Regulatory T-cell expansion during chronic viral infection is dependent on endogenous retroviral superantigens. Proc Natl Acad Sci U S A. 2011; 108(9):3677-82. PMC: 3048095. DOI: 10.1073/pnas.1100213108. View

Cabrera R, Tu Z, Xu Y, Firpi R, Rosen H, Liu C . An immunomodulatory role for CD4(+)CD25(+) regulatory T lymphocytes in hepatitis C virus infection. Hepatology. 2004; 40(5):1062-71. DOI: 10.1002/hep.20454. View

Betts R, Ho A, Kemeny D . Partial depletion of natural CD4⁺CD25⁺ regulatory T cells with anti-CD25 antibody does not alter the course of acute influenza A virus infection. PLoS One. 2011; 6(11):e27849. PMC: 3220674. DOI: 10.1371/journal.pone.0027849. View

Penaloza-MacMaster P, Kamphorst A, Wieland A, Araki K, Iyer S, West E . Interplay between regulatory T cells and PD-1 in modulating T cell exhaustion and viral control during chronic LCMV infection. J Exp Med. 2014; 211(9):1905-18. PMC: 4144726. DOI: 10.1084/jem.20132577. View

Saravia J, Chapman N, Chi H . Helper T cell differentiation. Cell Mol Immunol. 2019; 16(7):634-643. PMC: 6804569. DOI: 10.1038/s41423-019-0220-6. View

Zhu J, Jankovic D, Oler A, Wei G, Sharma S, Hu G . The transcription factor T-bet is induced by multiple pathways and prevents an endogenous Th2 cell program during Th1 cell responses. Immunity. 2012; 37(4):660-73. PMC: 3717271. DOI: 10.1016/j.immuni.2012.09.007. View

Lazarevic V, Chen X, Shim J, Hwang E, Jang E, Bolm A . T-bet represses T(H)17 differentiation by preventing Runx1-mediated activation of the gene encoding RORγt. Nat Immunol. 2010; 12(1):96-104. PMC: 3077962. DOI: 10.1038/ni.1969. View

Verma N, Hall B, Plain K, Robinson C, Boyd R, Tran G . Interleukin-12 (IL-12p70) Promotes Induction of Highly Potent Th1-Like CD4(+)CD25(+) T Regulatory Cells That Inhibit Allograft Rejection in Unmodified Recipients. Front Immunol. 2014; 5:190. PMC: 4023029. DOI: 10.3389/fimmu.2014.00190. View

10.

Cousens L, Orange J, Su H, Biron C . Interferon-alpha/beta inhibition of interleukin 12 and interferon-gamma production in vitro and endogenously during viral infection. Proc Natl Acad Sci U S A. 1997; 94(2):634-9. PMC: 19565. DOI: 10.1073/pnas.94.2.634. View

11.

Byrnes A, Ma X, Cuomo P, Park K, Wahl L, Wolf S . Type I interferons and IL-12: convergence and cross-regulation among mediators of cellular immunity. Eur J Immunol. 2001; 31(7):2026-34. DOI: 10.1002/1521-4141(200107)31:7<2026::aid-immu2026>3.0.co;2-u. View

12.

Levine A, Mendoza A, Hemmers S, Moltedo B, Niec R, Schizas M . Stability and function of regulatory T cells expressing the transcription factor T-bet. Nature. 2017; 546(7658):421-425. PMC: 5482236. DOI: 10.1038/nature22360. View

13.

Overacre-Delgoffe A, Chikina M, Dadey R, Yano H, Brunazzi E, Shayan G . Interferon-γ Drives T Fragility to Promote Anti-tumor Immunity. Cell. 2017; 169(6):1130-1141.e11. PMC: 5509332. DOI: 10.1016/j.cell.2017.05.005. 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.

Smeltz R, Chen J, Ehrhardt R, Shevach E . Role of IFN-gamma in Th1 differentiation: IFN-gamma regulates IL-18R alpha expression by preventing the negative effects of IL-4 and by inducing/maintaining IL-12 receptor beta 2 expression. J Immunol. 2002; 168(12):6165-72. DOI: 10.4049/jimmunol.168.12.6165. View

16.

Naka T, Tsutsui H, Fujimoto M, Kawazoe Y, Kohzaki H, Morita Y . SOCS-1/SSI-1-deficient NKT cells participate in severe hepatitis through dysregulated cross-talk inhibition of IFN-gamma and IL-4 signaling in vivo. Immunity. 2001; 14(5):535-45. DOI: 10.1016/s1074-7613(01)00132-7. View

17.

Lee S, Carrero J, Uppaluri R, White J, Archambault J, Lai K . Identifying the initiating events of anti-Listeria responses using mice with conditional loss of IFN-γ receptor subunit 1 (IFNGR1). J Immunol. 2013; 191(8):4223-34. PMC: 3874833. DOI: 10.4049/jimmunol.1300910. View

18.

Yang X, Bam M, Becker W, Nagarkatti P, Nagarkatti M . Long Noncoding RNA AW112010 Promotes the Differentiation of Inflammatory T Cells by Suppressing IL-10 Expression through Histone Demethylation. J Immunol. 2020; 205(4):987-993. PMC: 7415590. DOI: 10.4049/jimmunol.2000330. View

19.

Marshall H, Chandele A, Jung Y, Meng H, Poholek A, Parish I . Differential expression of Ly6C and T-bet distinguish effector and memory Th1 CD4(+) cell properties during viral infection. Immunity. 2011; 35(4):633-46. PMC: 3444169. DOI: 10.1016/j.immuni.2011.08.016. View

20.

Heninger A, Theil A, Wilhelm C, Petzold C, Huebel N, Kretschmer K . IL-7 abrogates suppressive activity of human CD4+CD25+FOXP3+ regulatory T cells and allows expansion of alloreactive and autoreactive T cells. J Immunol. 2012; 189(12):5649-58. DOI: 10.4049/jimmunol.1201286. View