Immune Regulation & Tolerance
Shen‐An Hwang, PhD
MSB 2.221E
Immune Regulation
Inflammation
Anti‐Inflammation
Immunological Tolerance
• Definition: State of unresponsiveness to a particular antigen
• Generally targets antigen receptor‐bearing cells, such as T‐ and B‐ cells
• Types
• Central: occurs during lymphocyte development
• Peripheral: induced in mature cells
• Consequences
• Apoptosis: clone is deleted (programmed cell death)
• Anergy: clone is inactivated (but not deleted)
• Regulation: everything else
Immunological Regulation
Key elements involved in immune regulation mechanisms
• Antigen presenting cells
• Regulatory cells
• Cytokine/chemokine environment
• Surface expression of regulatory molecules Central Tolerance: T‐cells
Central Tolerance: B‐cells
Regulatory Cells
• Death receptor expression
• Expression of inhibitory ligands
• Anti‐inflammatory cytokine production –
TGF‐1
Central Tolerance: T Regulatory Cells
Central Tolerance: B Regulatory Cells
Central Tolerance: Example
Peripheral Tolerance: Apoptosis
• Fas/FasL interaction
• Activation induced cell death
• Lack of growth factors
Peripheral Tolerance: Anergy
• Lack of secondary signal
• Presence of suppressive secondary signal
• Lack of helper cells
Immune Exhaustion
Peripheral Tolerance: Regulation
T‐cells:
• T‐regulatory cells
• T‐helper cells
• Cytokine production (eg. IL‐
10, TGF‐1)
• Direct cell‐cell contact (eg. CTLA‐
4/CD80)
Peripheral Tolerance: Regulation
B‐cells:
• B‐regulatory cells
• B‐effector cells
• Cytokine production (IL‐10)
Peripheral Tolerance: Regulation
Dendritic cells:
• Immature vs. mature
• Tissue specific DCs (e.g. mucosal DCs) • Cytokine production (e.g. TGF‐1)
• Alteration of surface marker expression (e.g. CD80/86)
Peripheral Tolerance: Regulation
Antigen sequestration:
• Immune privileged sites (CNS, eye, testes, ovaries, placenta)
• Exposure of privilege site antigens will result in autoimmunity
• Hidden antigens lead to escape of disease
Parameters that Influences Immunity
Age:
• Young
• Aged
Neurologic/Endocrine:
• Stress
• Nutrition
Antigen:
• Dose
• Route
• Antibody regulation
Examples of Tolerance at Work
Oral Tolerance
Dose of antigen
Low – favors regulatory T‐cells
High – favors anergy/apoptosis
Mechanism
Dendritic cells
Retinoic acid T‐regulatory cells Tolerance of Paternal Antigens
The paradox
• Fetal expression of paternal (foreign) antigens
• Shedding of trophoblast into maternal circulation
• Cellular debris from fetal tissue
• Presence of fetal cells in maternal circulation
Mechanism
• Immune stimulation by sperm exposure • Extravillous trophoblast cells lack of expression of antigen presentation molecules
• T‐regulatory cells – Maternal T‐reg numbers peak during the window when implantation can occur and during pregnancy
Immune Responses in Cancer
Cancer immunoediting
• Elimination
• Equilibrium
• Escape
Tumor microenvironment ‐‐ Concomitant immunity (transient) –
growth of tumor at one site despite rejection of subsequent introduction of the same tumor cells at a distant site Tolerance and Cancer
Mechanism
• Direct immune suppression by tumor cells • Expression of T‐cell inhibitory molecules
• Production of anti‐
inflammatory cytokines
• Alters recruitment of “suppressor” cell types
• T‐regulatory cells Allergy – Immune exhaustion
Immunological Tolerance
• Definition: State of unresponsiveness to a particular antigen
• Types
• Central
• Peripheral
• Consequences
• Apoptosis
• Anergy
• Regulation
Questions?