Lck Regulates IL-10 Expression in Memory-like Th1 Cells

Overview

Journal Eur J Immunol

Specialty Allergy & Immunology

Date 2010 Nov 10

PMID 21061443

Citations 7

Authors

Kyeorda L Kemp

Steven D Levin

Paul L Stein

Affiliations

Soon will be listed here.

Abstract

The Src family kinase Lck is thought to facilitate Th2 differentiation; however, its role in Th1 cells has not been well explored. Using mice that lack Lck in mature T cells, we find that lck(-/-) Th1 skewed cells have normal expression of T-bet and produce IFN-γ at WT levels. However, there is a 3-fold increase in IL-10 producing cells in the mutant cultures. These cells do not have elevated levels of IL-4, GATA3, IL-17 or Foxp3, indicating that they are not Th2, Th17, or Foxp3(+) T regulatory cells (Treg). Nor do these cells behave in a similar manner as the type 1 Treg. Most of the IL-10 in the lck(-/-) Th1 cultures is derived from the memory/activated subset, as the cytokine profile from Th1 cultures established from purified CD62L(+) (naïve) cells are similar to WT cells. Furthermore, this IL-10 expression appears to be dependent on IL-12 and correlates with elevated c-Maf. These data highlight a previously unappreciated role for Lck in regulating IL-10 in Th1 cells.

Citing Articles

The correlation between the Th17/Treg cell balance and bone health.

Zhu L, Hua F, Ding W, Ding K, Zhang Y, Xu C Immun Ageing. 2020; 17:30.

PMID: 33072163 PMC: 7557094. DOI: 10.1186/s12979-020-00202-z.

Molecular switches for regulating the differentiation of inflammatory and IL-10-producing anti-inflammatory T-helper cells.

Fang D, Zhu J Cell Mol Life Sci. 2019; 77(2):289-303.

PMID: 31432236 PMC: 11105075. DOI: 10.1007/s00018-019-03277-0.

Aryl Hydrocarbon Receptor Promotes IL-10 Expression in Inflammatory Macrophages Through Src-STAT3 Signaling Pathway.

Zhu J, Luo L, Tian L, Yin S, Ma X, Cheng S Front Immunol. 2018; 9:2033.

PMID: 30283437 PMC: 6156150. DOI: 10.3389/fimmu.2018.02033.

New insights into Blimp-1 in T lymphocytes: a divergent regulator of cell destiny and effector function.

Fu S, Yeh L, Chu C, Yen B, Sytwu H J Biomed Sci. 2017; 24(1):49.

PMID: 28732506 PMC: 5520377. DOI: 10.1186/s12929-017-0354-8.

Low level of Lck kinase in Th2 cells limits expression of CD4 co-receptor and S73 phosphorylation of transcription factor c-Jun.

Shebzukhov Y, Stanislawiak S, Bezhaeva T, Nedospasov S, Kuprash D Sci Rep. 2017; 7(1):2339.

PMID: 28539628 PMC: 5443812. DOI: 10.1038/s41598-017-02553-y.

References

Windhagen A, Anderson D, Carrizosa A, Williams R, Hafler D . IL-12 induces human T cells secreting IL-10 with IFN-gamma. J Immunol. 1996; 157(3):1127-31. View

Lee G, Kim S, Spilianakis C, Fields P, Flavell R . T helper cell differentiation: regulation by cis elements and epigenetics. Immunity. 2006; 24(4):369-79. DOI: 10.1016/j.immuni.2006.03.007. View

Saraiva M, Christensen J, Veldhoen M, Murphy T, Murphy K, OGarra A . Interleukin-10 production by Th1 cells requires interleukin-12-induced STAT4 transcription factor and ERK MAP kinase activation by high antigen dose. Immunity. 2009; 31(2):209-19. PMC: 2791889. DOI: 10.1016/j.immuni.2009.05.012. View

Ansel K, Djuretic I, Tanasa B, Rao A . Regulation of Th2 differentiation and Il4 locus accessibility. Annu Rev Immunol. 2006; 24:607-56. DOI: 10.1146/annurev.immunol.23.021704.115821. View

Tanchot C, Le Campion A, Leaument S, Dautigny N, Lucas B . Naive CD4(+) lymphocytes convert to anergic or memory-like cells in T cell-deprived recipients. Eur J Immunol. 2001; 31(8):2256-65. DOI: 10.1002/1521-4141(200108)31:8<2256::aid-immu2256>3.0.co;2-8. View

Heyeck S, Wilcox H, Bunnell S, Berg L . Lck phosphorylates the activation loop tyrosine of the Itk kinase domain and activates Itk kinase activity. J Biol Chem. 1997; 272(40):25401-8. DOI: 10.1074/jbc.272.40.25401. View

Das J, Chen C, Yang L, COHN L, Ray P, Ray A . A critical role for NF-kappa B in GATA3 expression and TH2 differentiation in allergic airway inflammation. Nat Immunol. 2001; 2(1):45-50. DOI: 10.1038/83158. View

Vieira P, Christensen J, Minaee S, ONeill E, Barrat F, Boonstra A . IL-10-secreting regulatory T cells do not express Foxp3 but have comparable regulatory function to naturally occurring CD4+CD25+ regulatory T cells. J Immunol. 2004; 172(10):5986-93. DOI: 10.4049/jimmunol.172.10.5986. View

Goldrath A, Bogatzki L, Bevan M . Naive T cells transiently acquire a memory-like phenotype during homeostasis-driven proliferation. J Exp Med. 2000; 192(4):557-64. PMC: 2193243. DOI: 10.1084/jem.192.4.557. View

10.

Rincon M, Enslen H, Raingeaud J, Recht M, Zapton T, Su M . Interferon-gamma expression by Th1 effector T cells mediated by the p38 MAP kinase signaling pathway. EMBO J. 1998; 17(10):2817-29. PMC: 1170622. DOI: 10.1093/emboj/17.10.2817. View

11.

Xu J, Yang Y, Qiu G, Lal G, Wu Z, Levy D . c-Maf regulates IL-10 expression during Th17 polarization. J Immunol. 2009; 182(10):6226-36. PMC: 2834209. DOI: 10.4049/jimmunol.0900123. View

12.

Pot C, Jin H, Awasthi A, Liu S, Lai C, Madan R . Cutting edge: IL-27 induces the transcription factor c-Maf, cytokine IL-21, and the costimulatory receptor ICOS that coordinately act together to promote differentiation of IL-10-producing Tr1 cells. J Immunol. 2009; 183(2):797-801. PMC: 2768608. DOI: 10.4049/jimmunol.0901233. View

13.

Raberger J, Schebesta A, Sakaguchi S, Boucheron N, Blomberg K, Berglof A . The transcriptional regulator PLZF induces the development of CD44 high memory phenotype T cells. Proc Natl Acad Sci U S A. 2008; 105(46):17919-24. PMC: 2584723. DOI: 10.1073/pnas.0805733105. View

14.

Garcia C, Wang H, Benakanakere M, Barrett E, Kinane D, Martin M . c-jun controls the ability of IL-12 to induce IL-10 production from human memory CD4+ T cells. J Immunol. 2009; 183(7):4475-82. PMC: 2849968. DOI: 10.4049/jimmunol.0901283. View

15.

Yamashita M, Hashimoto K, Kimura M, Kubo M, Tada T, Nakayama T . Requirement for p56(lck) tyrosine kinase activation in Th subset differentiation. Int Immunol. 1998; 10(5):577-91. DOI: 10.1093/intimm/10.5.577. View

16.

Nel A . T-cell activation through the antigen receptor. Part 1: signaling components, signaling pathways, and signal integration at the T-cell antigen receptor synapse. J Allergy Clin Immunol. 2002; 109(5):758-70. DOI: 10.1067/mai.2002.124259. View

17.

Mosser D, Zhang X . Interleukin-10: new perspectives on an old cytokine. Immunol Rev. 2009; 226:205-18. PMC: 2724982. DOI: 10.1111/j.1600-065X.2008.00706.x. View

18.

Barnden M, Allison J, Heath W, Carbone F . Defective TCR expression in transgenic mice constructed using cDNA-based alpha- and beta-chain genes under the control of heterologous regulatory elements. Immunol Cell Biol. 1998; 76(1):34-40. DOI: 10.1046/j.1440-1711.1998.00709.x. View

19.

Wildin R, Wang H, Forbush K, Perlmutter R . Functional dissection of the murine lck distal promoter. J Immunol. 1995; 155(3):1286-95. View

20.

Miller A, Wilcox H, Lai Z, Berg L . Signaling through Itk promotes T helper 2 differentiation via negative regulation of T-bet. Immunity. 2004; 21(1):67-80. DOI: 10.1016/j.immuni.2004.06.009. View