Tolerance Induction/MHC Restriction Flashcards
Are HEVs present in the thymus?
No
What two organs lack afferent lymphatics?
Spleen and thymus
What hormones are produced by the thymus?
Thymulin, thymosin alpha-1, thymopoietin
Thymulin produced by the thymus is dependent on what mineral?
Zinc
What happened when the thymus was removed from neonatal mice?
Degeneration of the anterior pituitary within 30 days
What is the function of thymulin that is produced by the thymus?
Involved with T cell maturation and differentiation (can also affect the neuroendocrine system
In what organ do T cells mature?
Thymus
What does it mean when T cells become mature?
Learn tolerance of self aka “central tolerance induction”
What does it mean when a T cell is “nude”?
Doesn’t express CD4, CD8, or TCR
Nude T cells enter the thymus from what location?
Bone marrow
Where in the thymus do nude T cells proliferate?
Cortex
Nude T cells are resistant to what process?
Apoptosis
Why are nude T cells resistant to apoptosis?
They express little or no Fas protein
What is expressed heavily on nude T cells that help protect them against apoptosis?
Bcl-2
What does it mean when a T cell becomes a double positive (DP) cell?
Possesses both CD4 and CD8 co-receptor molecules, lots of Fas protein on surface, and very little Bcl-2
What is the most common lymphocyte in the thymus (80%)?
Double positive (DP) cells
What two tests must a DP cell pass to avoid death?
MHC restriction
Tolerance to self
What is CD44?
Receptor for hyaluronic acid
Associated with thymocyte migration events
Considered a marker for T-cell activation
What is CD25?
Alpha chain of IL-2 receptor
Favors IL-2 thymocyte proliferation
Which DP test is considered “positive selection”?
MHC restriction
Which DP test is considered “negative selection”?
Tolerance to self
What occurs in the positive selection DP test?
T cell must only recognize peptides presented on MHCs
What occurs in the negative selection DP test?
T cell must not recognize self peptides
During which DP test does 95% of the maturing T cell deaths occur?
Positive selection (MHC restriction)
What cells check to see that T cells have receptors (TCR) that recognize one of the “self MHC” molecules (both I and II) during positive selection?
Cortical epithelial cells (CEC)
Where does the MHC restriction (positive selection) DP test occur?
Cortex of thymus
What happens to a T cell that recognizes peptides not presented by MHC molecules during positive selection?
Eliminated by apoptosis
When is a T cell referred to as a single positive cell (SP)?
After positive selection when it chooses either CD4 or CD8
What cells give the negative selection test?
Thymic dendritic cells and medullary thymic epithelial cells
After becoming single positive cells, where do the T cells migrate?
Medulla (to begin negative selection)
From where are thymic dendritic cells derived?
Bone marrow
Medullary thymic epithelial cells are related to what kind of cells (but have a different function)?
Cortical thymic epithelial cells
What is the negative selection DP test?
Thymic dendritic cells check to see if T cells recognize any of the self peptides displayed by MHC molecules on the cell’s surface
What is the goal of the negative selection DP test?
Eliminate T cells that recognize self peptides
Thymic dendritic cells only live about how long in the thymus?
1 week
Which test, positive or negative selection, prevents against auto immune disease?
Negative selection
Which cells express tissue specific proteins (antigens) that are unique to different tissues/organs in the body?
Medullary thymic epithelial cells
Which cells are responsible for cross presentation?
Medullary thymic epithelial cells
What cells are responsible for displaying self peptides on MHC molecules?
Thymic dendritic cells
Are intracellular proteins found on MHC I or MHC II?
MHC I (endogenous)
Do thymic dendritic cells sample the surrounding environment and present exogenous proteins on MHC I or MHC II?
MHC II
Medullary thymic epithelial cells engage in what process where they regularly enclose portions of their cytoplasm within a membrane?
Autophagy
When medullary thymic epithelial cells engage in autophagy, do they present protein samples on MHC I or MHC II molecules?
MHC II
What is the location for negative selection DP test?
Medulla
Do mature T cells recognize MHC-peptide complexes?
Yes
Self antigens are presented on which cells of the thymus during the negative selection test?
Thymic dendritic cells and medullary thymic epithelial cells
How long does the T cell maturation process take?
About 2 weeks
What is the pass rate of T cell maturation?
1/30
What happens to T cells that fail the maturation process?
Death by apoptosis and eaten up by macrophages
About how many double positive T cells begin a DP test each day?
60 million
What is the riddle of MHC restriction and tolerance induction?
How any T cells can possibly pass both the positive and negative selection
What is a rogue T cell?
One that got out but should have been killed
What is the issue with rogue T cells?
Likely to be self-reactive
How are natural regulatory T cells able to enter into secondary lymphoid organs?
Expression of a gene called Foxp3 enabling them to receive adhesion molecules that are used as “passports” for temporary travel
What do people who lack the Foxp3 protein end to die young of?
Autoimmune disease?
What is peripheral tolerance?
When a virgin T cell strays into abnormal tissues and encounters a rare self antigen that they weren’t exposed to in the thymus
What is a cell called when it recognizes its “cognate antigen” but does not receive the co-stimulatory signal?
Anergized
What happens to anergized cells?
They can’t function and die quickly
What is the “two key” activation required of T cells?
- Enough antigen to cluster receptors
2. Co-stimulatory signals
What kind of cells present lots of antigen and co-stimulatory (B7) molecules?
Antigen-presenting cells
What is the extra level of protection against naive T cells that travel outside their normal traffic pattern?
Peripheral tolerance
When a T cell passes even through peripheral tolerance, what is the next layer of defense?
Tolerance due to activation-induced cell death (AICD)
What is tolerance due to activation-induced cell death (AICD)?
When stimulated many times by self antigens, T cells then become more sensitive to ligation of their Fas proteins thereby leading them to be killed via apoptosis
What is central tolerance?
Positive and negative selection tests
What is tolerance by ignorance?
Restricted traffic patterns preventing self reaction of T cells
What is the order of T cell tolerance?
Central tolerance Tolerance by ignorance Tolerance induction in secondary lymphoid organs Peripheral tolerance Tolerance due to AICD
Most B cells are tolerized where?
Bone marrow
After testing, B cells that do not react to self are sent where?
To circulate blood and lymph
What happens to virgin B cells that venture into tissues that meet their cognant antigen but do not receive T cell help?
Either anergized or deleted
What is the process by which B cells modify their receptors after they have been activated?
Somatic hypermutation
Can T cells go through somatic hypermutation?
No, only B cells
What cells are the source of antigen for B cells in germinal centers?
Follicular dendritic cells
Are self antigens usually opsonized?
No
Where does B cell tolerance occur?
Bone marrow
What is receptor editing of B cells?
When B cells that recognize “self” are given a chance to change
About what percent of B cells successfully go through receptor editing?
25%
What happens to B cells that get into tissues and deviate from their usual restricted travel?
Either anergized or deleted
Where are iTregs developed?
MALT
What is the function of iTregs?
Restrain the immune system to keep it from over-reacting to foreign antigen in tissue
How do iTregs work?
By producing cytokines that suppress the immune response
Where are nTregs developed?
Thymus
What is the function of nTregs?
To provide protection against T cells in lymph nodes with the potential to react against self antigens that escaped negative selection in the thymus
What type of “Treg” is thought to require direct cell to cell contact and are antigen specific?
nTreg
What type of “Treg” is mainly CD4+?
nTreg
What type of “Treg” can be either CD4+ or CD8+?
S.N. Tregs
Which is considered a strong interaction: positive or negative selection?
Negative selection
Which is considered a weak interaction: positive or negative selection?
Positive selection
