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Regulatory T-cells and Autoimmunity

Bits Embryo Lecture. Regulatory T-cells and Autoimmunity. Uma Chandrasekaran Graduate Student, Medical College of Georgia. Basics. Components of Immune system:. “All cells of Immune system originate in the bone marrow .”. Basics …. Principles of innate and adaptive immunity.

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Regulatory T-cells and Autoimmunity

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  1. Bits Embryo Lecture Regulatory T-cells and Autoimmunity Uma Chandrasekaran Graduate Student, Medical College of Georgia

  2. Basics • Components of Immune system: “All cells of Immune system originate in the bone marrow.”

  3. Basics …. Principles of innate and adaptive immunity • Innate immunity: 1st line of defense - initial recognition of self-nonself. • Lack of Immunological memory • Adaptive Immunity: Random generation of Ag receptors Clonal selection – Basic operating principle Hall mark:Specificity & Immunological Memory

  4. Components of Adaptive response • T-cells & B-cells • 3 different types of T-cells: • 1) Helper T-cells (Th) :CD4+ T-cells • 2) Cytotoxic T-cells (Tc):CD8+T-cells 3) Regulatory T-cells(Tregs):CD4+ CD25+ T-cells

  5. Discovery of Tregs Normal Whole T cells Autoimmune Disease,IBD CD25– T cell SCID/Nude mice Loss of Tregs : Break of Self-Tolerance (Autoimmunity) * IBD –Inflammatory Bowel disease,SCID-Severe Combined Immunodeficiency mice

  6. Markers of Tregs • Cell Surface markers • CD4 + T cells • CD 25 + (high) • Intracellular markers • Foxp3 • CTLA4 (high) TR - Regulatory T-cell TE - Effector T-cell APC-Antigen Presenting Cell

  7. CD 25 :T-cell activation marker CD 25 : IL-2 receptor  Chain So,CD25 is not an exclusive marker of Tregs

  8. Foxp3 : Treg cell lineage Specification factor IPEX : X-linked immunodeficiency syndrome associated with autoimmune disease in multiple organs (Humans) Scurfy Mice: Fatal X-linked lymphoproliferative disease similar to IPEX Foxp3 Mutation Foxp3, transcription factor expressed specifically in Tregs *Immune dysregulation.polyendocrinopathy,enteropathy,X-linked syndrome

  9. Functional Characteristics of Tregs • Immunosuppressive – dampen both innate & adaptive immune response Thus ,function as critical mediators of self-toleranceandImmune homeostasis.

  10. Potential Clinical applications of Tregs Target condition Approach Organ transplant, Autoimmunity, allergy Transfer of Tregs CD4+ 25 + Treg function Removal of Tregs/block their function Cancer, Infectious disease CD4+ 25 + Treg function

  11. Current research focus in Treg Immunology • Expansion /Enrichment of naturally occurring Tregs - Naturally occurring Tregs constitute only 5-10% of CD4 T cells - as they are anergic cells, difficult to expand invitro. • Specific markers for Tregs - CD25+ and Foxp3 are also expressed on activated cells • Understanding the mechanism of immunosuppression

  12. References • Sakaguchi S. J.Exp.Med,Vol 197,No.4,2003 397-401. • Fehervari Z et al.J Clin Invest 114:1209-1217(2004). • Rudensky A.Nat Immunol 2005. • Sakaguchi S.Annu Rev Immunol 2004,22:531-562. • Janeway and Travers ,Immunobiology,6th Edition.

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