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Immune Tolerance. Dr. Prakash Nagarkatti Associate Dean for Basic Science 733-3180 pnagark@uscmed.sc.edu. Self-nonself discrimination. Non-self or foreign. Self. No response. Strong response. Tolerance. Tolerance--->specific unresponsiveness triggered by previous exposure to Ag.
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Immune Tolerance Dr. Prakash Nagarkatti Associate Dean for Basic Science 733-3180 pnagark@uscmed.sc.edu
Self-nonself discrimination Non-self or foreign Self No response Strong response
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:
Burnet’s Hypothesis:(1949) 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.
stain-A bone marrow Tolerance Medawar proves Burnet’s Hypothesis: Strain A Strain B The above result was specific. • Burnett & Medawar won Nobel Prize in 1960.
Radiation Bone-marrow Chimeras A 1000R B Lymphoid cells--> strain A B Non lymphoid---> strain B This procedure is used in cancer patients.
Tolerance • Why is it imp. to study tolerance? • Autoimmunity • Cancer • Transplantation • Infections • Vaccines
Factors which affect response Favor immune response Favor tolerance Factors affecting tolerance:role of antigen Physical form of antigen Large, aggregated, complex molecules soluble, aggregate-free, simple small molecules Antigen processing properly processed improperly processed Subcutaneous or intra-muscular Oral or, sometimes, intravenous Route of injection Very large or very small dose Dose of antigen Optimal dose
Factors which affect response Favor immune response Favor tolerance Factors affecting tolerance:role of antigen Age of responding animal Adult, immunologically mature Newborn (mice) Immunologically immature Fully differentiated, Memory Differentiation state of cells 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.
T cell Development in the thymus Dendritic cells Cortical epithelium MHC Class I and II High TCR V Low TCR CD4 V CD4 CD4-CD8-TCR- CD8 V TCR BM Stem cell Thymocyte CD8 Mature T cell Negative selection Positive selection
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.
Role of anti-idiotypic Ab in tolerance. Anti-idiotype Ag epitope 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 Fas+ Fas- Normal Fas L Fas Autoimmunity and lymphoproliferative disease Fas L
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.
