Tolerance Induction and MHC Restriction

Question 1

T or F. There are no incoming lymphs in the thymus

Answer 1

T! just like the spleen

Question 2

where do ‘nude’ t cells proliferate?

Answer 2

at the cortex of the thymus

• they begin rearranging their alpha and beta chains on their TCRs
• successful? then these T cells become dressed with TCRs (including CD3) and low levels of both CD8 and CD4
• DPs

Question 3

‘nude’ T cells have little to no ____ on their surface and express high levels of ____

Answer 3

Fas; Bcl-2

Question 4

Bcl-2

Answer 4

cellular protein that protects against apoptosis; nude T cells highly resistant to apoptosis

Question 5

in contrast to ‘nude’ T cells, “fully dressed” T cells…

Answer 5

have a lot of Fas on their surfaces and produce very little Bcl-2

Question 6

MHC restriction

Answer 6

• positive selection
• first exam
• DP T cells are examined by epithelial cells in cortex
• recognize host MHC (I/II)?
• correct answer is yes!
• if not, apoptosis

Question 7

peptides generated by the cortical thymic epithelial cells

Answer 7

through process of autophagy

Question 8

central tolerance induction

Answer 8

• negative selection
• survivors of MHC restriction begin to display one co-receptor (SP)
• second exam
• tolerant toward self-antigens?
• first part: mTEC test SP T cells for their ability to recognize self peptides obtained from common proteins found in all host cells and tissue-specific self peptides; correct answer is NO!
• TDC (unique DCs) from bone marrow; also test SP T cells to see if they recognize common self peptides within MHC molecules on the TDC; answer is NO!

Question 9

Positive selection

Answer 9

needs a relatively weak interaction between TCR and [MHC + self-peptide] displayed on cortical thymic epithelial cells

Question 10

Negative selection

Answer 10

needs a strong interaction between a TCR and [MHC+self peptide] displayed on a thymic dendritic cell and/or medullary thymic epithelial cell

Question 11

Activation of T cells

Answer 11

• after leaving thymus
• needs a strong interaction between the TCR and the MHC+peptide displayed on professional APCs (lymph node or at site of battle)

Question 12

Peripheral tolerance induction

Answer 12

• by ignorance
• by nTregs in secondary lymphoid organs
• by anergy
• by activation
• induced cell death (AICD)

Question 13

when T cells remain functionally ignorant

Answer 13

some virgin T cells that do recognize self antigens are not activated bc self antigens are rare in secondary lymphoid organs where they are restricted to travelling (lymphocyte trafficking)

Question 14

nTregs in secondary lymphoid organs

Answer 14

• self-antigens increase when tissue injury
• nTregs’ function is antigen-specific (recognize same self-peptide as the escapee T cell
• activated by an APC presenting its cognate peptide, then it:
  > limits ability of that APC to access escapee that recognizes same cognate peptide
  > causes down-reg of co-stim molecules on that APC

Question 15

for a T cell to become an nTreg, a gene called ______ must be activated

Answer 15

Foxp3

Question 16

What would happen if an escapee virgin T cell violates traffic restrictions and enters into tissue where it can react with its cognate self antigen?

Answer 16

• virgin T cells need [MHC+peptide] AND a co-stim molecule (like B7) to be activated
• if an escapee self-reactive T cell encounters ONLY the [MHC+self peptide] signal from a cell in the tissues, it will be ‘neutered’ = anergized -> death

Question 17

What if an escapee gets out of the secondary lymphoid organs and enters into tissue where it can react with its cognate self peptide in MHC and get a co-stim signal required for activation?

Answer 17

• immune system uses same mechanism it uses to down-reg T cells once the battle is over = AICD
• AICD is used to eliminate these escapee virgin T cells which are ‘overstimulated’ by constant exposure to self antigen

Question 18

How are self-reactive B cells eliminate?

Answer 18

• BM
• after B cells mix and match gene segments, specificity of their BCR is tested for rxn with self antigens
• auto-reactive B cells are given a second chance to rearrange their gene segments = receptor editing

Question 19

What if B cells escape the tolerance screening in the bone marrow?

Answer 19

• B cells normally are geographically restricted to secondary lymphoid tissue or bone marrow by their ‘passports’
• B cells can be anergized or deleted if they are stimulated by self-antigen without T help

Question 20

where are NK cells screened?

Answer 20

BM! - make sure they do see at least one kind of MHC in a person; if not = anergized!