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.