Cellular Basis for Immunological Tolerance Flashcards
What is the result of loss of tolerance to self-antigens?
Autoimmune diseases
What is a major problem concerning chronic infections and tolerance?
Chronic infections can lead to immunological tolerance against the infections agents and therefore recurring infections
Where is central tolerance developed?
In the thymus: T-cells that react too strongly to self-antigens are eliminated
.How do regulatory T cells play a role in peripheral tolerance?
Regulatory T cells are professional T cells that are designed to impose suppression on other T cells and accessory cells
What are myeloid derived suppressor cells (MDSCs)
MDSCs are a group of myeloid cells that become potent immunoregulatory cells when exposed to inflammatory cytokines such as IFN-gamma and kill activated T cells to prevent further stimulation
What happens to T cells that are inappropriately or insufficiently stimulated?
They become anergic
How does AIRE aid the the process of central tolerance?
AIRE gene enables thymic stromal cells to express non-thymic genes. It allows for the presentation of self antigen to developing thymocytes. T cells that react too strongly die via apoptosis
Where are regulatory T cells generated in the thymus?
Hassall’s corpuscle
Where is AIRE expressed?
Primarily in the medulla of the thymus
Where are nTregs generated?
nTregs are generated in the thymus and impose suppression of other immune cells (mainly T cells).
Since they are generated in the thymus, their antigen diversity is limited to mostly “self-antigens”
What sorts of environmental factors manipulate iTregs?
food, commensal organisms, pathogens and tumors
What two cytokines drive the differentiation of naive T cells into iTregs?
TGFbeta and IL2
Presence of what cytokines inhbit the induction of iTregs?
inflammatory cytokines, primarily IL6
Which vitamins serve as co-factors for the induction of iTregs
Vitamin A and D
What are Tr1 cells?
Tr1 cells produce the immunosuppressive cytokine IL-10
Which two cytokines induce the differentiation of Tr1 cells?
TGFbeta and IL-27. High levels of IL-10 are also sufficient to produce Tr1 cells.
They are NOT Foxp3
WHat is IPEX?
Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX): syndrome characterized by systemic autoimmunity, typically beginning in the first year of life. IPEX is cased by loss of dysfunction of FOXp3.
What happens to T cells that are presented antigens in the absence of the crucial “second signal” - stimulation from CD28 (ligand is CD80/CD86).
They become anergic
What is the purpose of CTLA-4?
CTLA-4 is expressed by T cells after activation and competes with CD28 for binding to B7 (and has a higher affinity for B7 than CD28).
In the natural sequence of antigen action of T cells, there is progressive increasing production of CTLA-4 as a regulatory mechanism to prevent runaway T cell proliferation
What happens to people with deficient CTLA-4?
They die in utero, due to lethal autoimmune diseases
How do clinicians try to suppress graft vs host disease after bone marrow transplants?
Though inhibition of co-stimulation done by using CTLA-4 in a “trans” manner to block T cell activation from the outside.
This is accomplished through the use of man-made biologic modified CTLA-4-Ig, which is now also tested in clinical trials to treat autoimmune disorders
