Lecture 14/15 T Cell Development Positive and Negative Selection Flashcards
Where does Class II processing Occur?
In acidic endosomes with Cathepsins S and L being the most important in proteolytic cleavage of peptides.
CLIP
Class II associated invariant chain peptide prevents other peptides from binding class II.
Why is invariant chain important?
Invariant chain prevents premature binding of peptides to Class II; binds to alpha and beta chains w/clip
What enzyme cleaves Invariant chain?
Cathepsin S
Class I (exogenous or endogenous)
endogenous
Class II (exogenous or endogenous)
exogenous
Invariant chain (Ii) (exogenous or endogenous)
exogenous; Ii binds to MHC II and keeps peptides from binding prematurely
Lysosomal hydrolases (exogenous or endogenous)
exogenous; endosome and lysosome fuse;
TAP1/TAP2 (exogenous or endogenous)
endogenous (associated with Class I only)
Transport of vesicles from the ER to the golgi (exogenous or endogenous)
Both Class I and Class II MHC are made in the ER; both MHC II and I are both processed by the golgi
Proteosomes (exogenous or endogenous)
MHC I; endogenous
phagocytosis (exogenous or endogenous)
exogenous
calnexin (exogenous or endogenous)
endogenous Chaperone for MHC I stabilizes class I
CLIP (exogenous or endogenous)
exogenous MHC II; associated with invariant chain
Tapasin (exogenous or endogenous)
endogenous
In what organ to T Cells mature?
Thymus. Thymocytes originate from the bone marrow
What are the two different T cell lineages?
ab vs gd
EBF, E2A and Pax 5 are the important transcription factors for a progenitor cell to commit to B cell development. What transcription factor is important for T cell commitment?
Notch-1
Thymic Cortex
contains cortical epithelial cells; immature thymocytes
Thymic medulla
contain medullary epithelial cells; mature thymocytes
Nude mouse
Defect in cortical epithelium, so thymus doesn’t develop
SCID
Severe combined immunodeficiency caused by defect in genes that encode for RAG1/2; VDJ recombination can not occur.
DN1
Express CD44 and Kit (Reacts w/SCF)
DN2
Express CD44 and now CD25, begin to rearrange b chain of TCR (Db to Jb) become CD44’˚
DN3
CD44’˚, Kit’˚, CD25 continue to rearrange b chain (Vb to DJb) and pair with preTalpha
DN4
CD44-, CD25-, Pre-T Cell receptor complex w CD3 allows cells to proliferate and to block further b-chain rearrangement.
Where does positive selection occur?
Deep cortex; with interaction with thymic cortical epithelial cells expressing MHC interact with DP cells- positive selection takes place.
What is the first checkpoint in thymocyte development?
B chain rearrangement; preTalpha signaling; and CD4/CD8 at double negative
Positive Selection
Takes place in the Cortext; double positive thymocytes receive survial signals after interacting with specialized APCs in the thymus - Thymic epithelial cells
Positive Selection and Thymic environment
T cells are positively selected based on the MHC expressed by Thymic epithelial cells
Where does positive selection occur?
By Thymic cortical epithelial cells in the Cortex
3 Hypotheses to Explain Transition to single positive thymocytes
1) CD4 or CD8 is turned off randomly, no relation to TCR
2) Interaction between TCR, MHC I, and CD8 instructs cell to differentiate into CD8+ Class I restricted T cell. (and vice versa)
3) Interaction between TCR, MHC II and CD4 in a continuous signal instructs cell to differentiate into CD4+ class II restricted T cell, cell with CD8 gets an interrupted TCR signal and survives with IL-7 signals
Where does negative selection occur?
In the medulla, bone marrow derived DCs and Macrophages are the most effective in mediating negative selection; cells that react strongly with self MHC: self peptide combinations are deleted during negative selection; results in tolerance
Where do thymocytes become single positive?
Post-positive selection in the cortex.
How does tolerance in the periphery occur?
Negative selection in secondary lymphoid organs, regulation by Treg,
AIRE
Autoimmune Regulator; a transcription factor that induces the expression of many tissue specific proteins in the medulla on medullary thymic epithelial cells; mutations in AIRE lead to autoimmune disease against a variety of organ-APECED
What role does Macrophages play in thymocyte apoptosis?
Macrophages phagocytose thymocytes that have experienced apoptosis.
Scid/scid mouse
lack recombination machinery, cannot produce T Cell receptor
Nu/nu mouse
lack thymus or thymic epithelial cells, cannot produce T Cells.
Where are DN thymocytes found?
Subcapsular region
