RA Mediated T-reg Differentiation

IntroductionIntroduction

T-regulatory cells (T-regs) are a small subset of CD4+ T-cells that exhibit strong down regulation of immune system activity in their local environment. They are distinguished from other CD4+ T-cells by the expression of FOXP3, a gene regulator. ^[1] These cells have been shown to differentiate from CD4+ T-helper cells upon exposure to the following cytokines: tumor growth factor β (TGF-β), Interleukin-2 (IL-2) and retinoic acid (RA). ^[2] Both TGF-β and IL-2 are used in other immune system differentiation, however, RA has been shown to bias T-cells to the T-reg phenotype. ^[3] When acting upon T-reg cells, RA acts as the ligand for the Retinoic Acid Receptor-α (RARα) / Retinoid X Receptor-α (RXRα) heterodimer. This heterodimer is of the nuclear receptor family, and each chain consists of the same three part structure: a Ligand binding domain (LBD), a DNA binding domain (DBD), and a hinge region connecting the two binding domains. ^[4]

Ligand Binding Domain

RARα-RXRα Heterodimer

RARα-RXRα Ligand Interactions

DNA Binding Domain

RXRα-DNA Interactions

DR-5 Specificity

Biological SignificanceBiological Significance

ReferencesReferences

↑ Ochs HD, Oukka M, Torgerson TR. TH17 cells and regulatory T cells in primary immunodeficiency diseases. J Allergy Clin Immunol. 2009 May;123(5):977-83; quiz 984-5. PMID:19410687 doi:10.1016/j.jaci.2009.03.030
↑ Moore C, Fuentes C, Sauma D, Morales J, Bono MR, Rosemblatt M, Fierro JA. Retinoic acid generates regulatory T cells in experimental transplantation. Transplant Proc. 2011 Jul-Aug;43(6):2334-7. PMID:21839265 doi:10.1016/j.transproceed.2011.06.057
↑ Moore C, Fuentes C, Sauma D, Morales J, Bono MR, Rosemblatt M, Fierro JA. Retinoic acid generates regulatory T cells in experimental transplantation. Transplant Proc. 2011 Jul-Aug;43(6):2334-7. PMID:21839265 doi:10.1016/j.transproceed.2011.06.057
↑ Kumar R, Thompson EB. The structure of the nuclear hormone receptors. Steroids. 1999 May;64(5):310-9. PMID:10406480

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William Bailey, Michal Harel, Jaime Prilusky, Alexander Berchansky

[1] Ochs HD, Oukka M, Torgerson TR. TH17 cells and regulatory T cells in primary immunodeficiency diseases. J Allergy Clin Immunol. 2009 May;123(5):977-83; quiz 984-5. PMID:19410687 doi:10.1016/j.jaci.2009.03.030

[2] Moore C, Fuentes C, Sauma D, Morales J, Bono MR, Rosemblatt M, Fierro JA. Retinoic acid generates regulatory T cells in experimental transplantation. Transplant Proc. 2011 Jul-Aug;43(6):2334-7. PMID:21839265 doi:10.1016/j.transproceed.2011.06.057

[3] Moore C, Fuentes C, Sauma D, Morales J, Bono MR, Rosemblatt M, Fierro JA. Retinoic acid generates regulatory T cells in experimental transplantation. Transplant Proc. 2011 Jul-Aug;43(6):2334-7. PMID:21839265 doi:10.1016/j.transproceed.2011.06.057

[4] Kumar R, Thompson EB. The structure of the nuclear hormone receptors. Steroids. 1999 May;64(5):310-9. PMID:10406480

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