Conditioning of Naive CD4(+) T Cells for Enhanced Peripheral Foxp3 Induction by Nonspecific Bystander Inflammation

Overview

Journal Nat Immunol

Date 2016 Jan 12

PMID 26752376

Citations 11

Authors

Lucas J Thompson

Jen-Feng Lai

Andrea C Valladao

Tennille D Thelen

Zoe L Urry

Steven F Ziegler

Affiliations

Soon will be listed here.

Abstract

Inflammation induced during infection can both promote and suppress immunity. This contradiction suggests that inflammatory cytokines affect the immune system in a context-dependent manner. Here we show that nonspecific bystander inflammation conditions naive CD4(+) T cells for enhanced peripheral Foxp3 induction and reduced effector differentiation. This results in inhibition of immune responses in vivo via a Foxp3-dependent effect on antigen-specific naive CD4(+) T cell precursors. Such conditioning may have evolved to allow immunity to infection while limiting subsequent autoimmunity caused by release of self-antigens in the wake of infection. Furthermore, this phenomenon suggests a mechanistic explanation for the idea that early tuning of the immune system by infection affects the long-term quality of immune regulation.

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References

Haribhai D, Williams J, Jia S, Nickerson D, Schmitt E, Edwards B . A requisite role for induced regulatory T cells in tolerance based on expanding antigen receptor diversity. Immunity. 2011; 35(1):109-22. PMC: 3295638. DOI: 10.1016/j.immuni.2011.03.029. View

Takahashi R, Nishimoto S, Muto G, Sekiya T, Tamiya T, Kimura A . SOCS1 is essential for regulatory T cell functions by preventing loss of Foxp3 expression as well as IFN-{gamma} and IL-17A production. J Exp Med. 2011; 208(10):2055-67. PMC: 3182063. DOI: 10.1084/jem.20110428. View

Schmitz M, Weber A, Roxlau T, Gaestel M, Kracht M . Signal integration, crosstalk mechanisms and networks in the function of inflammatory cytokines. Biochim Biophys Acta. 2011; 1813(12):2165-75. DOI: 10.1016/j.bbamcr.2011.06.019. View

Mills K . TLR-dependent T cell activation in autoimmunity. Nat Rev Immunol. 2011; 11(12):807-22. DOI: 10.1038/nri3095. View

Gonzalez-Navajas J, Lee J, David M, Raz E . Immunomodulatory functions of type I interferons. Nat Rev Immunol. 2012; 12(2):125-35. PMC: 3727154. DOI: 10.1038/nri3133. View

Miyao T, Floess S, Setoguchi R, Luche H, Fehling H, Waldmann H . Plasticity of Foxp3(+) T cells reflects promiscuous Foxp3 expression in conventional T cells but not reprogramming of regulatory T cells. Immunity. 2012; 36(2):262-75. DOI: 10.1016/j.immuni.2011.12.012. View

Trinchieri G . Cancer and inflammation: an old intuition with rapidly evolving new concepts. Annu Rev Immunol. 2012; 30:677-706. DOI: 10.1146/annurev-immunol-020711-075008. View

Bilate A, Lafaille J . Induced CD4+Foxp3+ regulatory T cells in immune tolerance. Annu Rev Immunol. 2012; 30:733-58. DOI: 10.1146/annurev-immunol-020711-075043. View

Wang Y, Swiecki M, Cella M, Alber G, Schreiber R, Gilfillan S . Timing and magnitude of type I interferon responses by distinct sensors impact CD8 T cell exhaustion and chronic viral infection. Cell Host Microbe. 2012; 11(6):631-42. PMC: 3572910. DOI: 10.1016/j.chom.2012.05.003. View

10.

Koch M, Thomas K, Perdue N, Smigiel K, Srivastava S, Campbell D . T-bet(+) Treg cells undergo abortive Th1 cell differentiation due to impaired expression of IL-12 receptor β2. Immunity. 2012; 37(3):501-10. PMC: 3501343. DOI: 10.1016/j.immuni.2012.05.031. View

11.

Yamane H, Paul W . Early signaling events that underlie fate decisions of naive CD4(+) T cells toward distinct T-helper cell subsets. Immunol Rev. 2013; 252(1):12-23. PMC: 3578301. DOI: 10.1111/imr.12032. View

12.

Wilson E, Yamada D, Elsaesser H, Herskovitz J, Deng J, Cheng G . Blockade of chronic type I interferon signaling to control persistent LCMV infection. Science. 2013; 340(6129):202-7. PMC: 3704950. DOI: 10.1126/science.1235208. View

13.

Teijaro J, Ng C, Lee A, Sullivan B, Sheehan K, Welch M . Persistent LCMV infection is controlled by blockade of type I interferon signaling. Science. 2013; 340(6129):207-11. PMC: 3640797. DOI: 10.1126/science.1235214. View

14.

Liu Y, Carlsson R, Comabella M, Wang J, Kosicki M, Carrion B . FoxA1 directs the lineage and immunosuppressive properties of a novel regulatory T cell population in EAE and MS. Nat Med. 2014; 20(3):272-82. DOI: 10.1038/nm.3485. View

15.

Srivastava S, Koch M, Pepper M, Campbell D . Type I interferons directly inhibit regulatory T cells to allow optimal antiviral T cell responses during acute LCMV infection. J Exp Med. 2014; 211(5):961-74. PMC: 4010906. DOI: 10.1084/jem.20131556. View

16.

Stelekati E, Shin H, Doering T, Dolfi D, Ziegler C, Beiting D . Bystander chronic infection negatively impacts development of CD8(+) T cell memory. Immunity. 2014; 40(5):801-13. PMC: 4114317. DOI: 10.1016/j.immuni.2014.04.010. View

17.

Osokine I, Snell L, Cunningham C, Yamada D, Wilson E, Elsaesser H . Type I interferon suppresses de novo virus-specific CD4 Th1 immunity during an established persistent viral infection. Proc Natl Acad Sci U S A. 2014; 111(20):7409-14. PMC: 4034239. DOI: 10.1073/pnas.1401662111. View

18.

Lyons A . Analysing cell division in vivo and in vitro using flow cytometric measurement of CFSE dye dilution. J Immunol Methods. 2000; 243(1-2):147-54. DOI: 10.1016/s0022-1759(00)00231-3. View

19.

Taniguchi T, Takaoka A . A weak signal for strong responses: interferon-alpha/beta revisited. Nat Rev Mol Cell Biol. 2001; 2(5):378-86. DOI: 10.1038/35073080. View

20.

Barchet W, Cella M, Odermatt B, Asselin-Paturel C, Colonna M, Kalinke U . Virus-induced interferon alpha production by a dendritic cell subset in the absence of feedback signaling in vivo. J Exp Med. 2002; 195(4):507-16. PMC: 2193622. DOI: 10.1084/jem.20011666. View