Cellular Basis for Immunological Tolerance Flashcards
Define immunological tolerance and give some examples
Non-responsiveness to specific Ag
Tolerance to self-Ag, food particles, commensal bacteria, pregnancy
What is an example of a hyper-immune disorder?
Allergy
What is an example of an autoimmune disease?
IBD
How do tumors hijack the immune system?
They create an environment that the immune system recognizes as self, and is thus tolerant to it
What is central tolerance?
elimination of T cells that are reactive to Ag presented in the thymus - self Ag
What are three mechanisms of peripheral tolerance?
Tregs
Myeloid Derived Suppressor Cells (MDSC)
Inappropriate or insufficient co-stimulation of a T cell in presence of its Ag
How are Tregs involved in peripheral tolerance?
Tregs are professional T cells that are designed to impose suppression to other T cells and accessory cells
How are MDSCs involved in peripheral tolerance?
A group of myeloid cells become potent immunoregulatory cells when exposed to pro-inflammatory cytokines such as IFN-gamma and will kill activated T cells to prevent further proliferation
Define anergy and explain how it is involved in peripheral tolerance
When a T cell is inappropriately or insufficiently co-stimulated in the presence of its Ag, the will become anergic, or, non-responsive to further stimulation
What does intrathymic clonal deletion do?
deletes cells that are autoreactive (have high affinity to Ag present in the thymus)
How is AIRE involved in central tolerance?
It produces tissue specific self Ag that can be presented to developing thymocytes
What do cells that have an intermediate affinity to self become?
they are not eliminated by negative selection, but rather mature into Foxp3+ Tregs
Where are Tregs generated?
Hassall’s corpuscle
What does loss of AIRE result in?
Autoimmune Polyendocrine Syndrome (ARS) - endocrine organs are destroyed by Ab and lymphocytes
What are MDSCs?
Cells of lymphoid origin that can suppress T cell responses
To what do MDSCs respond?
pre-existing inflammations, activated by pro-inflammatory cytokines such as IFN-gamma (produced by Th1 and CD8+ - found in inflammatory states)
How do MDSCs suppress T cell response?
Release NO and arginase (will deprive the cell of arginine)
what are nTregs?
cells generated in the thymus that suppress other immune cells, mainly T cells
What is important about the fact that nTregs are generated in the thymus?
their Ag diversity is mainly limited to self Ag
what are iTregs?
These Tregs can be manipulated by the environment, commensal bacteria, pathogen, tumors
What induces iTregs and what cytokines play a role?
iTregs are induced by APCs in the mucosa, and require Vit A and D. IL-2, TGF-beta are involved in iTreg stimulation.
IL-6 is inhibitory
What are Tr1 cells?
TGF-beta and IL-27 induces these cells, which are NOT Foxp3+
produce IL-10
What will result from the failure of peripheral tolerance?
IPEX (Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked):
caused by loss or dysfunction of foxp3, leads to systemic autoimmunity
What is clonal Anergy?
the state of T cells when they are not responsive to Ag
When does clonal anergy occur?
When T cells are presented Ag in the absence of co-stimulation via CD28
Who expresses the ligand for CD28? (and what is it?)
The ligand for CD28 is CD80/86 and is expressed by a select group of APCs
What is CTLA-4?
CTLA-4 is expressed by T cells after activation and competes with CD28 for B7 binding - CTLA-4 has higher affinity for B7, and will thus bind preferentially over CD28
CTLA-4 also recruits signaling molecules that suppress T cells and blocks Ag activation
how can we use CTLA-4 in BMT and autoimmune diseases?
give CTLA-4Ig which can block T cell activation from the outside
