Lecture 11: Cellular basis for immunological tolerance Flashcards
Define immunological tolerance:
non-responsiveness to specific antigens
What are some examples of tolerance?
antigens from self-tissues, foods, commensal bacterium, pregnancy
What is the relationship between tumors and immunological tolerance?
tumors impair anti-tumor immunity
What is the relationship between tumors and immunological tolerance?
tumors impair anti-tumor immunity
Tolerance is induced by what two mechanisms?
1) Central
2) Peripheral
What is central tolerance?
elimination of T cells that are reactive to antigens present in the thymus (self antigens)
What is peripheral tolerance?
- Tregs (impose suppression to other T cells and accessory cells)
- MDSCs (myeloid derived suppressor cells) myeloid cells that become potent immunoregulatory cells when exposed to inflammatory cytokines like IFNy and kill activated T cells to prevent further stimulation
- Anergy (when T cells are stimulated in a manner that are not “complete” cells become non-responsive to further stimulation
What gene allows for thymic negative selection?
AIRE
enables stromal cells to express non-thymic genes and present self-antigens to developing thymocytes
What is Hassall’s corpuscles important for?
site for generation of regulatory T cells
(cells that have intermediate affinity to self-antigens and are not eliminated by negative selection mature into Foxp3 Tregs)
What happens in patients without AIRE?
severe auto-recessive genetic autoimmune disorder
What are nTregs?
professional T regulatory cells that impose suppression of other immune cells (T cells)
nTregs antigen diversity is limited to _______
self antigens (generated in the thymus due to high affinity against antigens present in the thymus)
What are iTregs?
Tregs that can be manipulated by environment (food), commensals, pathogens, tumor
iTregs are induced by APCs that are present where?
mucosal environment (intestine)
What are cofactors to induce iTregs?
Vitamin A and/or D
What inflammatory cytokine is INHIBITORY for induction of iTregs?
IL-6
Which 2 cytokines play a major role in iTreg development?
IL-2
TGFb
What are Tr1 cells?
produce immunosuppressive IL-10
and are produced by high amounts of IL-10
Which two cytokines induce development of Tr1 cells?
TGFb
IL-27
Are Tr1 cells Foxp3+?
NO
What disease results from failure of peripheral tolerance?
IPEX (immune dysregulation, polyendocirnopathy, enteropathy, X-linked)
What is IPEX?
systemic autoimmunity (in the 1st year of life) characterized by LOSS of Foxp3
What are MDSCs?
Myeloid Derived Suppressor Cells (heterogeneous population of cells that are defined by myeloid origin and ability to potently suppress T cell responses)
What cytokine can activate MDSCs?
IFNy (usually around from pre-existing inflammation)
