Immune Tolerance�

Dr. Prakash Nagarkatti

Associate Dean for Basic Science

733-3180

pnagark@gw.med.sc.edu

Self-nonself discrimination

Self

No response

Strong response

Non-self

or foreign

Tolerance

• Tolerance--->specific unresponsiveness triggered by previous exposure to Ag.
• Natural Tolerance (self tolerance): Unresponsiveness to self Ags.
• Acquired tolerance:

Unresponsiveness to foreign Ags.

Tolerance

Tolerance in non-identical cattle twins:

Tolerance

• During neonatal stage of life, or when immune system is developing, all Ags present are recognized as self.
• Immune system becomes tolerant to these Ags.
• How is tolerance accomplished?
• By clonal deletion--cells which come across self-Ag undergo apoptosis.

Burnet’s Hypothesis:(1949)

Tolerance

Medawar proves Burnet’s Hypothesis:

The above result was specific.

• Burnett & Medawar won Nobel Prize in 1960.

Mouse Chimera

Radiation Bone-marrow Chimeras

1000R

Lymphoid cells-->

strain A

Non lymphoid---> strain B

A

B

B

This procedure is used in cancer patients.

Tolerance

• Why is it imp. to study tolerance?
• Autoimmunity
• Cancer
• Transplantation
• Infections
• Vaccines

Factors affecting tolerance:�role of antigen

Very large or very small dose

Optimal dose

Dose of antigen

Physical form of antigen

Large, aggregated, complex molecules

soluble, aggregate-free, simple small molecules

Antigen processing

properly processed

improperly processed

Route of injection

Subcutaneous or intra-muscular

Oral or, sometimes, intravenous

Factors affecting tolerance:�role of antigen

Age of responding animal

Adult, immunologically mature

Newborn (mice)

Immunologically immature

Differentiation state of cells

Fully differentiated, Memory

Undifferentiated B cell with only IgM, T cells in the thymic cortex

Mechanisms of tolerance

• There are multiple mechanisms of tolerance.
• Clonal deletion.
• Regulatory T cells (formerly called suppressor T cells).
• Anti Idiotypic Abs.

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T cell Development in the thymus

V

V

V

BM Stem cell

Thymocyte

Mature T cell

CD4

CD8

Low TCR

High TCR

CD8

CD4

TCR

CD4-CD8-TCR-

Positive selection

Negative selection

Cortical epithelium

Dendritic cells

MHC

Class I and II

Regulatory T cells

• Several different regulatory T-cell subsets have been described.
• The CD4+ regulatory T cells have been categorized into two major subgroups:
• Forkhead box P3 (Foxp3)+CD4+CD25+ regulatory T cells which develop in the thymus and are present in normal mice and healthy individuals from birth
• Inducible regulatory T cells, which are generated in the periphery under various tolerogenic conditions.

Foxp3

• Foxp3, an X chromosome–encoded forkhead transcription factor family member, is indispensable for the differentiation of regulatory T cells.
• Genetic mutations in Foxp3 in humans leads to development of a severe and rapidly fatal autoimmune disorder known as Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX)syndrome.
• Foxp3 mutations lead to massive lymphoproliferation, diabetes, exfoliative dermatitis, thyroiditis and enteropathy.

Regulatory T cells

• Defective regulatory T cells in genetic diseases:
• Patients with Wiskott–Aldrich syndrome, autoimmune polyglandular syndrome type 2 and autoimmune lymphoproliferative syndrome are the few autoimmune diseases caused by known genetic defects. These patients have also defects in regulatory T cells.
• Regulatory T cells can be used in the treatment of autoimmune diseases in future.

Regulatory cells

• The precise mode of action of regulatory T cells is not clear.
• Cell-cell contact and soluble factors such as IL-10 or TGF-β play a role.
• Regulatory T cells play a crucial role in oral tolerance. Ex: Colitis can be prevented by transfer of regulatory T cells.

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Role of anti-idiotypic Ab in tolerance.

epitope

Ag

Idiotype

Anti-idiotype

Activation-induced Cell Death(AICD)

Plays a key role

in peripheral

T cell tolerance.

Defiency of Fas

or FasL triggers

Lympho-

Proliferative

Disease.

Defect in Fas or FasL triggers Autoimmunity

Fas

Normal

Fas L

Fas

Autoimmunity and

lymphoproliferative

disease

Fas L

Fas+

Fas-

Summary

• Immune system recognizes both self and non-self.
• Immune tolerance is a specific mechanism through which the host tries to evade responding to self-Ags.
• Clonal deletion and Regulatory T cells are the primary mechanisms.
• Breakdown of tolerance leads to autoimmune disorders.

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