Flashcards in Lecture 13, Cell Basis of Tolerance Deck (45):
What is another term for negative selection?
What are the 3 methods/cells of peripheral tolerance?
1. Regulatory T cells
2. Myeloid Derived Suppressor Cells (MDSCs)
3. Clonal Anergy (T cells)
What do Myeloid Derived Suppressor Cells (MDSCs) do?
What cytokine tends to activate them?
- APCs that can block T cell responses (while MDSC is presenting Ag to the T cell)
"To protect the host from the harmful effects of excessive immune stimulation during acute and chronic infections, and to limit the generation of autoimmune responses towards tissue antigens released by trauma"
- e.g. IFN-γ
- Often tumor-associated
Describe the process of clonal anergy.
- When T cells are stimulated in a manner that are not “complete,” cells become non-responsive to further stimulation.
What is the very general function of Tregs?
Suppress immune response
What is the AIRE transcription factor responsible for?
- Gives APCs self-antigen from non-thymic parts of the body to present to developing thymocytes for negative selection in the thymic medulla.
Loss of function of AIRE genes could lead to what disease?
Autoimmune Polyendocrine Syndrome (APS)
- Endocrine organs are destroyed by ABs and lymphocytes. (failure of central tolerance)
After central tolerance is complete, what other process do T cells continually undergo to make sure the do not react to self?
In response to IFN-gamma, what do MDSCs produce that effectively suppresses T cell activation?
NO and arginase
Name the 3 types of Tregs.
1. nTregs (Natural)
2. iTregs (Inducable)
3. Tr1 cells
Where are nTregs generated?
Are they FOXP3 + or - ?
What cytokine is essential for their maintenance?
From what cells do nTregs come from?
How does their background serve their function?
Where in the thymus does this take place?
- A group of thymocytes that have reactivity against *self-ag's are converted into nTregs.
- These are self-reactive clones, but they don’t attack, don’t acquire effector functions to promote immune responses. Instead, activated by self ag to acquired selective activity.
- Hassalls corpuscles
Recall: what are Hassall's corpuscles?
*What occurs there?
Groups of epithelial cells within the thymic medulla.
- Site for generation of Tregs
What molecule do Hassall's corpuscles give off that helps w/the differentiation of FOXP3+ Tregs?
Thymic stromal lymphopoietin (TSLP)
Recall: Mutations in the FOXP3 gene causes what dz?
Immunodysregulation, Polyendocrinopathy, and Enteropathy, X-linked (IPEX)
- Suffer from multiple tissue damages caused by self-reactive T cells (due to lack of Tregs)
What factors can induce iTregs?
Are they FOXP3 + or - ?
What 2 cytokines are critical for their maintenance?
- Environment (food), commensal organisms, pathogens and tumors
- TGF-beta and IL-2
What cytokine is critical for the induction of both Th17 cells and iTregs?
What other cytokine will decide whether the helper T cell will become an iTreg vs a Th17 cell?
- IL-6 (IL-6+ will create Th17, IL-6- will created iTreg)
Generally, how do Th17 cells differ in function from iTregs?
Th17 cells are the opposite of iTregs.
- Th17 cells are the most potent pro-inflammatory T cells.
- Th17 cells also require TGF-beta, but requires pro-inflammatory IL-6, often produced by activated macrophages
What 2 vitamins act as cofactors do induce iTregs?
Vitamin A (retinoic acid, RA) and/or D
Are Tr1 cells FOXP3 + or - ?
*What is the major cytokine they release?
What is their overall function?
- Immunosuppression and maintenance of tolerance
What vitamin is linked to the generation of Tr1 cells (by upregulating IL-10)?
Tr1 cells develop in response to antigenic stimulation when what 2 cytokines are present in the environment?
TGF-beta and IL-27
While Tr1 cells mainly use IL-10 to enhance their functions, FOXP3+ Tregs use what 2 cytokines?
IL-10 and TGF-beta
What signaling receptor/ligand combo is absent when clonal anergy occurs w/T cells?
Anergy is induced when antigen is presented (TCR + MHC) in the absence of co-stimulatory signal (CD28, on T cell).
- Ligand of CD28 are B7.1 (CD80) and B7.2 (CD86)
How come CD28 on T cells binding B7 limits the risk of false stimulation?
B7 is only present on professional APCs, thus limiting what can stimulate a T cell.
What's the name of the process that occurs if a T cell cannot bind B7 on its APC target cell in the thymus?
Silencing process (degradation of signaling molecules)
What cells produce CTLA-4?
What receptor does CTLA-4 bind?
How does CTLA-4 function?
What does it recruit?
- Competes w/CD28 of T cell for binding at B7 (has higher affinity than CD28, so it will win out)
- Also recruits signaling molecules that suppress TCR signaling and blocks ag-activation.
(critical role in immune homeostasis)
How could you take advantage of CTLA-4 to treat autoimmune diseases such as Graft-Versus-Host Disease and psoriasis?
Man-made CTLA4-IG can be given exogenously to mimic CTLA4, thus inhibiting the T cell activation and improving symptoms of GVH and psoriasis.
How could CTLA-4 be taken advantage of in "Immune Checkpoint Blockade"?
What major disease category would be good to treat this way?
Many costimulatory molecules (e.g. CTLA4) work in an inhibitory manner to T cells. For cancer immunotherapy, blocking these inhibitory molecules provoked robust anticancer immune responses (increased T cell stimulation)
- Novel cancer tx
Gene: AIRE: Phenotype of mutant or knockout mouse?
Destruction of endocrine organs by ABs, lymphocytes
Gene: AIRE: Mechanism of failure of tolerance?
Failure of central tolerance
Gene: AIRE: Human disease?
Autoimmune potyendocrine syndrome (APS)
Gene: FoxP3: Phenotype of mutant or knockout mouse?
Multi-organ lymphocytic infiltrates, wasting
Gene: FoxP3: Mechanism of failure of tolerance?
Deficiency of regulatory T cells
Gene: FoxP3: Human disease?
Gene: 1L-2: IL-2R: Phenotype of mutant or KO mouse?
Inflammatory bowel disease: antierythrocyte and anti-DNA
Gene: 1L-2: IL-2R: Mechanism of failure of tolerance?
Defective development, survival or function of regulatory T cells
Gene: 1L-2: IL-2R: Human disease?
Gene: CTLA-4: Phenotype of mutant or knockout mouse?
Lymphoproliferation; T cell infiltrates in multiple organs
Gene: CTLA-4: Mechanism of failure of tolerance?
Failure of anergy in CD4+ T cells
Gene: CTLA-4: Human disease?
CTLA-4 polymorphisms associated with several
Gene: IL-10: Phenotype of mutant or knockout mouse?
Inflammatory bowel disease
Gene: IL-10: Mechanism of failure of tolerance?
Failure of T cell and accessory cell suppression against commensal bacterium
Gene: IL-10: Human disease?
Polymorphism link to IBD, various cancers