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

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: 1 st 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 (T h ) :CD4+ T-cells 2) Cytotoxic T-cells (T c ):CD8+T-cells 3) Regulatory T-cells(Tregs):CD4+ CD25+ T-cells

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

6. Markers of Tregs Cell Surface markers -CD4 + T cells - CD 25 + (high) Intracellular markers -Foxp3 - CTLA4 (high) T R - Regulatory T-cell T E - 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) *Immune dysregulation.polyendocrinopathy,enteropathy,X-linked syndrome Foxp3 Mutation Foxp3, transcription factor expressed specifically in Tregs Scurfy Mice: Fatal X-linked lymphoproliferative disease similar to IPEX

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

10. Potential Clinical applications of Tregs CD4 + 25 + Treg function CD4 + 25 + Treg function Target conditionApproach Organ transplant, Autoimmunity, allergy Cancer, Infectious disease Transfer of Tregs Removal of Tregs/block their 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 1.Sakaguchi S. J.Exp.Med,Vol 197,No.4,2003 397-401. 2.Fehervari Z et al.J Clin Invest 114:1209-1217(2004). 3.Rudensky A.Nat Immunol 2005. 4.Sakaguchi S.Annu Rev Immunol 2004,22:531-562. 5.Janeway and Travers,Immunobiology,6 th Edition.