regulatory t-cells and autoimmunity uma chandrasekaran graduate student, medical college of georgia...
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Regulatory T-cells and Autoimmunity
Uma ChandrasekaranGraduate Student,
Medical College of Georgia
Bits Embryo Lecture
Basics
Components of Immune system:
“All cells of Immune system originate in the bone marrow.”
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
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
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)
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
CD 25 :T-cell activation marker
CD 25 : IL-2 receptor Chain
So,CD25 is not an exclusive marker of Tregs
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
Functional Characteristics of Tregs
Immunosuppressive – dampen both innate & adaptive immune response
Thus ,function as critical mediators of
self-tolerance and Immune homeostasis.
Potential Clinical applications of Tregs
CD4+ 25 + Treg function
CD4+ 25 + Treg function
Target condition Approach
Organ transplant,Autoimmunity,allergy
Cancer,Infectious disease
Transfer of Tregs
Removal of Tregs/block their function
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
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,6th Edition.