Type 1 regulatory T cell

Type 1 regulatory cells or Tr1 (TR1) cells are a class of regulatory T cells participating in peripheral immunity as a subsets of CD4+ T cells . Tr1 cells regulate tolerance towards antigens of any origin. Tr1 cells are self or non-self antigen specific and their key role is to induce and maintain peripheral tolerance[1] and suppress tissue inflammation in autoimmunity and graft vs. host disease.[2]

Characterization and surface molecules

The specific cell-surface markers for Tr1 cells in humans and mice are CD4+ CD49b+LAG-3+ CD226+ from which LAG-3+ and CD49b+ are indispensable.[3] LAG-3 is a membrane protein on Tr1 cells that negatively regulates TCR-mediated signal transduction in cells. LAG-3 activates dendritic cells (DCs) and enhances the antigen-specific T-cell response which is necessary for Tr1 cells antigen specificity.[3][4][5] CD49b belongs to the integrin family and is a receptor for many (extracellular) matrix and non-matrix molecules. CD49b provides only little contribution to the differentiation and function of Tr1 cells.[3]

They characteristically produce high levels of IL-10, IFNy, IL-5 and also TGF- β but no IL-4 nor IL-2[6] Production of IL-10 is also much more rapid than its production of other T-helper cell types.[6]

Tr1 cells do not constitutively express FOXP3[7] but only transiently, upon their activation and in smaller amounts than CD25+ FOXP3+ regulatory cells.[8] FOXP3 is not required for Tr1 induction nor for its function[1]. They also express repressor of GATA-3 (ROG), while CD25+ FOXP3+ regulatory cells do not.[9] ROG then dowregulates GATA-3, a characteristic transcription factor for Th2 cells.

Tr1 cells express high levels of regulatory factors, such as glucocorticoid-induced tumor necrosis factor receptor (GITR), OX40 (CD134), and tumor-necrosis factor receptor (TNFRSF9).[8] Resting human Tr1 cells express Th1 associated chemokine receptors CXCR3 and CCR5, and Th2-associated CCR3, CCR4 and CCR8.[8] Upon activation, Tr1 cells migrate preferentially in response to I-309, a ligand for CCR8.[8]

Mechanism of Tr1-mediated suppression

The suppressing and tolerance-inducing effect of Tr1 cells is mediated mainly by cytokines. The other mechanism as cell to cell contact, modulation of dendritic cells, metabolic disruption and cytolysis is however also available to them.[1] In vivo Tr1 cells need to be activated, to be able to exert their regulatory effects.[6]

Mechanisms of suppression
  • Cytokines mediated

Tr1 cells secrete large amount of suppressing cytokines IL-10 and TGF-β.[7] IL-10 directly inhibits T cells by blocking its production of IL-2, IFNy and GM-CSF and have tolerogenic effect on B cells and support differentiation of other regulatory T cells.[10] IL-10 indirectly downregulates MHC II molecules and co-stimulatory molecules on antigen-presenting cells (APC) and force them to upregulate tolerogenic molecules such as ILT-3, ILT-4 and HLA-G.[11]

  • Cell to cell contact:

Type 1 regulatory T cells poses inhibitory receptor CTLA-4 through which they exert suppressor function.[12]

  • Metabolic disruption:

Tr1 cells can express ectoenzymes CD39 and CD73 and are suspected of generating adenosine which suppresses effector T cell proliferation and their cytokine production in vitro.[13]

  • Cytolitic activity:

Tr1 cells can both express Granzyme A and granzyme B. It was shown recently, that Tr1 cells, in vitro and also ex vivo, specifically lyse cells of myeloid origin, but not other APC or T or B lymphocytes.[14] Cytolysis indirectly suppresses immune response by reducing numbers of myeloid-origin antigen presenting cells.

Differentiation

Tr 1 cells are inducible, arising from precursors naive T cells. They can be differentiated ex vivo and in vivo.[15] The ways of Tr1 cells induction in vivo, ex vivo and in vitro differ and also envelop many different approaches but the molecular mechanism appears to be conserved.

IL-27, together with TGF-β induces IL-10–producing regulatory T cells with Tr1-like properties cells.[16][17] IL-27 alone can induce IL-10-producing Tr1 cells, but in the absence of TGF-β, the cells produce large quantities of both IFN-γ and IL-10.[18] IL-6 and IL-21 also plays a role in differentiation as they regulate expression of transcription factors necessary for IL-10 production, which is believed to start up the differentiation itself later on.

Proposed transcription biomarkers for type 1 regulatory cells differentiation are:[18]

  • musculoaponeurotic fibrosarcoma(c-Maf)
  • the aryl hydrocarbon receptor (AhR)
  • interferon regulatory factor 4 (IRF4)
  • the repressor of GATA-3 (ROG)
  • early growth response protein 2 (Egr-2)

Expression of these transcriptional factors are driven by IL-6 in IL-21 and IL-2 dependant manner.

Clinical manifestation and application

Tr1 cells possess huge clinical potential in means to prevent, block and even cure several T cells mediated diseases, including GvHD, allograft rejection, autoimmunity and chronic inflammatory diseases. The first successful tests were performed on mouse models[19][20] and on humans as well.[20][21]

Transplantation research has shown, that donor Tr1 in response to recipient alloantigens, was found to correlate with the absence of GvHD after bone marrow transplantation, while decreased numbers of Tr1 markedly associated with severe GvHD.[21] Decreased levels of IL-10 CD4+ producing cells were also observed in inflamed synovium and peripheral blood of patients with rheumatoid arthritis.[7]

Phase I/II of clinical trials of Tr1 cell treatment concerning Crohn's disease have been successful and appear to be safe and do not lead to a general immune suppression.[20][21]

References
  1. Gregori, Silvia; Goudy, Kevin S.; Roncarolo, Maria Grazia (2012-02-29). "The Cellular and Molecular Mechanisms of Immuno-Suppression by Human Type 1 Regulatory T Cells". Frontiers in Immunology. 3: 30. doi:10.3389/fimmu.2012.00030. ISSN 1664-3224. PMC 3342353. PMID 22566914.
  2. Chihara, Norio; Madi, Asaf; Karwacz, Katarzyna; Awasthi, Amit; Kuchroo, Vijay K. (2016-04-01). "Differentiation and Characterization of Tr1 Cells". Current Protocols in Immunology. 113: 3.27.1–3.27.10. doi:10.1002/0471142735.im0327s113. ISBN 9780471142737. ISSN 1934-368X. PMC 5933847. PMID 27038462.
  3. Gagliani, Nicola; Magnani, Chiara F.; Huber, Samuel; Gianolini, Monica E.; Pala, Mauro; Licona-Limon, Paula; Guo, Binggege; Herbert, De'Broski R.; Bulfone, Alessandro (June 2013). "Coexpression of CD49b and LAG-3 identifies human and mouse T regulatory type 1 cells". Nature Medicine. 19 (6): 739–746. doi:10.1038/nm.3179. ISSN 1546-170X. PMID 23624599.
  4. El Mir, S.; Triebel, F. (2000-06-01). "A soluble lymphocyte activation gene-3 molecule used as a vaccine adjuvant elicits greater humoral and cellular immune responses to both particulate and soluble antigens". Journal of Immunology. 164 (11): 5583–5589. doi:10.4049/jimmunol.164.11.5583. ISSN 0022-1767. PMID 10820232.
  5. Triebel, Frédéric (December 2003). "LAG-3: a regulator of T-cell and DC responses and its use in therapeutic vaccination". Trends in Immunology. 24 (12): 619–622. doi:10.1016/j.it.2003.10.001. ISSN 1471-4906. PMID 14644131.
  6. Levings, M. K.; Roncarolo, M. G. (July 2000). "T-regulatory 1 cells: a novel subset of CD4 T cells with immunoregulatory properties". The Journal of Allergy and Clinical Immunology. 106 (1 Pt 2): S109–112. doi:10.1067/mai.2000.106635. ISSN 0091-6749. PMID 10887343.
  7. Yudoh, K.; Matsuno, H.; Nakazawa, F.; Yonezawa, T.; Kimura, T. (March 2000). "Reduced expression of the regulatory CD4+ T cell subset is related to Th1/Th2 balance and disease severity in rheumatoid arthritis". Arthritis and Rheumatism. 43 (3): 617–627. doi:10.1002/1529-0131(200003)43:3<617::AID-ANR19>3.0.CO;2-B. ISSN 0004-3591. PMID 10728756.
  8. Gregori et al.: Type 1 regulatory T (Tr1) cells: from the bench to the bedside. Journal of Translational Medicine 2012 10(Suppl 3):I7.
  9. Cobbold, Stephen P.; Nolan, Kathleen F.; Graca, Luis; Castejon, Raquel; Le Moine, Alain; Frewin, Mark; Humm, Susan; Adams, Elizabeth; Thompson, Sara (December 2003). "Regulatory T cells and dendritic cells in transplantation tolerance: molecular markers and mechanisms". Immunological Reviews. 196: 109–124. doi:10.1046/j.1600-065X.2003.00078.x. ISSN 0105-2896. PMID 14617201.
  10. Scott-Taylor, Tim H.; O'B Hourihane, Jonathan; Strobel, Stephan (September 2010). "Correlation of allergen-specific IgG subclass antibodies and T lymphocyte cytokine responses in children with multiple food allergies". Pediatric Allergy and Immunology. 21 (6): 935–944. doi:10.1111/j.1399-3038.2010.01025.x. ISSN 1399-3038. PMID 20444160.
  11. Manavalan, John S.; Rossi, Paola C.; Vlad, George; Piazza, Flavia; Yarilina, Anna; Cortesini, Raffaello; Mancini, Donna; Suciu-Foca, Nicole (July 2003). "High expression of ILT3 and ILT4 is a general feature of tolerogenic dendritic cells". Transplant Immunology. 11 (3–4): 245–258. doi:10.1016/S0966-3274(03)00058-3. ISSN 0966-3274. PMID 12967778.
  12. Bacchetta, Rosa; Sartirana, Claudia; Levings, Megan K.; Bordignon, Claudio; Narula, Satwant; Roncarolo, Maria-Grazia (August 2002). "Growth and expansion of human T regulatory type 1 cells are independent from TCR activation but require exogenous cytokines". European Journal of Immunology. 32 (8): 2237–2245. doi:10.1002/1521-4141(200208)32:8<2237::AID-IMMU2237>3.0.CO;2-2. ISSN 0014-2980. PMID 12209636.
  13. Mandapathil, Magis; Szczepanski, Miroslaw J.; Szajnik, Marta; Ren, Jin; Jackson, Edwin K.; Johnson, Jonas T.; Gorelik, Elieser; Lang, Stephan; Whiteside, Theresa L. (2010-09-03). "Adenosine and prostaglandin E2 cooperate in the suppression of immune responses mediated by adaptive regulatory T cells". The Journal of Biological Chemistry. 285 (36): 27571–27580. doi:10.1074/jbc.M110.127100. ISSN 1083-351X. PMC 2934624. PMID 20558731.
  14. Magnani, Chiara F.; Alberigo, Giada; Bacchetta, Rosa; Serafini, Giorgia; Andreani, Marco; Roncarolo, Maria Grazia; Gregori, Silvia (June 2011). "Killing of myeloid APCs via HLA class I, CD2 and CD226 defines a novel mechanism of suppression by human Tr1 cells". European Journal of Immunology. 41 (6): 1652–1662. doi:10.1002/eji.201041120. ISSN 1521-4141. PMC 3116154. PMID 21469116.
  15. Battaglia, Manuela; Gregori, Silvia; Bacchetta, Rosa; Roncarolo, Maria-Grazia (April 2006). "Tr1 cells: from discovery to their clinical application". Seminars in Immunology. 18 (2): 120–127. doi:10.1016/j.smim.2006.01.007. ISSN 1044-5323. PMID 16464609.
  16. Awasthi, Amit; Carrier, Yijun; Peron, Jean P. S.; Bettelli, Estelle; Kamanaka, Masahito; Flavell, Richard A.; Kuchroo, Vijay K.; Oukka, Mohamed; Weiner, Howard L. (December 2007). "A dominant function for interleukin 27 in generating interleukin 10-producing anti-inflammatory T cells". Nature Immunology. 8 (12): 1380–1389. doi:10.1038/ni1541. ISSN 1529-2916. PMID 17994022.
  17. "Suppression of autoimmune inflammation of the central nervous system by interleukin 10 secreted by interleukin 27-stimulated T cells (PDF Download Available)". ResearchGate. Retrieved 2017-08-18.
  18. Zeng, Hanyu; Zhang, Rong; Jin, Boquan; Chen, Lihua (September 2015). "Type 1 regulatory T cells: a new mechanism of peripheral immune tolerance". Cellular & Molecular Immunology. 12 (5): 566–571. doi:10.1038/cmi.2015.44. ISSN 2042-0226. PMC 4579656. PMID 26051475.
  19. Bluestone, Jeffrey A.; Thomson, Angus W.; Shevach, Ethan M.; Weiner, Howard L. (August 2007). "What does the future hold for cell-based tolerogenic therapy?". Nature Reviews. Immunology. 7 (8): 650–654. doi:10.1038/nri2137. ISSN 1474-1733. PMID 17653127.
  20. Roncarolo, Maria-Grazia; Battaglia, Manuela (August 2007). "Regulatory T-cell immunotherapy for tolerance to self antigens and alloantigens in humans". Nature Reviews. Immunology. 7 (8): 585–598. doi:10.1038/nri2138. ISSN 1474-1733. PMID 17653126.
  21. Weston, L. E.; Geczy, A. F.; Briscoe, H. (2005-11-07). "Production of IL-10 by alloreactive sibling donor cells and its influence on the development of acute GVHD". Bone Marrow Transplantation. 37 (2): 207–212. doi:10.1038/sj.bmt.1705218. ISSN 0268-3369. PMID 16284610.
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