12 T Cell Tolerance Flashcards
True or false? self reactive t cells are controlled by central but not peripheral tolerance?
false—they are by both
True or false? self reactive t cells are controlled by central but not peripheral tolerance?
false—they are by both
What do medullary epithelial cells express?
self peptides in the context of MHCI and MHCII
What drives thymocyte selection?
affinity for MHC/antigen complex
What locations all play roles in thymocyte selection?
cortical epithelial cells, medullary epithelial cells and resident dendritic cells—(basically anywhere in the thymus when there is a functional TCR alpha and beta presented)
Mice with deficient MHC class II can’t produce what?
CD4 Tcells–defects in ability to activate CD4 thymocytes during selection
What area of the thymus presents the largest number of proteins from the human body for selection?
Medullary thymic epithelial cells
What drives the promiscuous expression of proteins for thymocyte selection?
transcriptional regulator AIRE
What picks up proteins from blood stream for thymocyte selection?
thymus resident dendritic cells
What presents periphery self antigens to the thymus?
Peripheral dendritic cells (food antigens and commensal bacteria antigens too)
Most important mechanisms of peripheral tolerance? [3]
immune privilege
costimulation —>anergy and cell death
regulatory T-cells
What mechanisms drive immune privilege? [5]
- Physical barriers
- low expression of MHC
- Expression of suppressive cytokines
- Expression of Fas ligands
- Increased number of regulatory T-cells
What mechanisms drive immune privilege? [5]
- Physical barriers
- low expression of MHC
- Expression of suppressive cytokines
- Expression of Fas ligands
- Increased number of regulatory T-cells
What do medullary epithelial cells express?
self peptides in the context of MHCI and MHCII
What drives thymocyte selection?
affinity for MHC/antigen complex
What locations all play roles in thymocyte selection?
cortical epithelial cells, medullary epithelial cells and resident dendritic cells—(basically anywhere in the thymus when there is a functional TCR alpha and beta presented)
Infections and inflammation leads to up regulation of what in antigen presenting cells? [costimulatory protein with CD28]
B7
What area of the thymus presents the largest number of proteins from the human body for selection?
Medullary thymic epithelial cells
What drives the promiscuous expression of proteins for thymocyte selection?
transcriptional regulator AIRE
What picks up proteins from blood stream for thymocyte selection?
thymus resident dendritic cells
What presents periphery self antigens to the thymus?
Peripheral dendritic cells (food antigens and commensal bacteria antigens too)
Most important mechanisms of peripheral tolerance? [3]
immune privilege
costimulation —>anergy and cell death
regulatory T-cells
Damage to an immune privileged organ can cause what?
autoimmunity
What mechanisms drive immune privilege? [5]
- Physical barriers
- low expression of MHC
- Expression of suppressive cytokines
- Expression of Fas ligands
- Increased number of regulatory T-cells
What 3 signals are required for Tcell full activation?
1: TCR/co-receptors–specificity
2: costimulatory receptors—-suppress auto-reactivity
3: cytokines—differentiation
What signal in absence of the what other signal causes cell death or anergy in the T cell?
signal 1 in absence of signal 2.
What is the primary costimulatory molecule for naive T cells?
CD28–activated upon binding B7-1 and B7-2
What happens to mice deficient in CD28?
normal early responses to infection, but do not have T cell expansion, differentiation and function
Infections and inflammation leads to up regulation of what in antigen presenting cells? [costimulatory protein with CD28]
B7
The simultaneous activation of both the TCR and CD28?
cytokine production, proliferation, and protein expression
What protein is expressed several days after initial TCR/CD28 activation, binds B7, and inhibits CD28 function?
CTLA-4
What happens in over expression of CTLA-4?
immune evasion of several types of cnacer
What happens in defects of CTLA-4?
autoimmunity
what are critical for suppressing T cell responses before and following infection, control auto reactive tells and shut down pathogen specific T cell responses?
Regulatory T cells
Do naive CD4 T cells or Regulatory T cells have a stronger reactivity to self peptide- MHC class II?
regulatory T cells
Do naive CD4 T cells or regulatory T cells make cytokines IL-10 and TGF beta?
Regulatory—Naive make IL-2
What is the key transcriptional regulator for regulatory T cells?
FOXP3- epigenetically
When are regulatory T cells produced?
during positive and negative selection in the thymus—T cells with a moderate level of self reactivity differentiate into regulatory T cells
What is the purpose of inducible regulatory T cells?
limit damage to surrounding tissue
What are the 6 mechanisms regulatory T cells suppress effector T cell function?
- direct inhibition of DC via CTLA4
- Production of suppressive cytokines
- Binding of IL-2 by CD25
- Direct lysis of effector T cells
- Eliminate extracellular ATP, produce adenosine
- Forming Gap junctions with effector T cells
Overexpression of inflammatory cytokines or under expression of suppressive cytokines can cause??
multiple autoimmune disorders
Defects in proteins required for controlling central and peripheral tolerance can also drive the initiation and progression of what?
autoimmune disorders
