Type 1 regulatory T cell

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Type 1 regulatory cells or Tr1 (T_R1) cells are a class of

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, IFN-γ, IL-5 and also TGF- β but neither IL-4 nor IL-2.^[6] Production of IL-10 is also much more rapid than its production by other T-helper cell types.^[6]

Tr1 cells do not constitutively express

Tr1 cells express high levels of regulatory factors, such as glucocorticoid-induced tumor necrosis factor receptor (

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, IFN-γ 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

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