L13 Regulation of Immunity

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IL-2 stimulates

T cell diff

IL-12 drives T cell diff toward

Th1
(prod by macros)

IL-4 drives T cell diff toward

Th2

Ig of 1º response?

IgM

Ig of 2º response?

IgG

Treg cells are CD___+

CD4+/CD25+

T cell release ____ that drives B cell prolif

IL-4

What is immunologic tolerance?

"unresponsiveness to self antigens"

What percentage of cells dev't from hematopoetic precursors never make it to maturity?

95%

Central tolerance

caused by anergy (functional unresponsiveness) or apoptosis of immature cells that are self-reactive

Foreign antigens are presented at the...

2º lymphoid organs: spleen, lymph nodes, Peyer's patches....

Peripheral tolerance: T cell that recognize self antigen in peripheral tissue...

1. apoptosis, or
2. anergy, or
3. Treg suppression

Anergy is caused by

• +1st signal: antigen recognition, but -2nd signal: costimulation (or suppressor costim, e.g. CTLA-4), or
• low affinity peptide ligand

CTLA-4 is found on _, and binds _

• T cells
• B7 on APCs (↑ p microbe encounter)
• inhibitory fn

CD28 is found on _, and binds _

• T cells
• B7 on APCs (↑ p microbe encounter)
• stim fn

CD40L is found on _, and binds _

• activated T cells
• CD40 on B cells

LFA-1 is found on _, and binds _

• T cells
• ICAM-1 on APCs

Repeated activation of T cells by self-ag or recognition of self-ag s 2nd signal stimulates...

apoptosis

In CD4+ T cells, repeated activation results in co-expression of ___ and ___, which causes ____

• Fas (CD95) and FasL- death receptor
• apoptosis caused by caspase activation when Fas-FasL bind; can occur with itself or nearby cell

in vivo anergy

an adaptation to persistent Ag

Clonal anergy

growth arrest state that maintain cell in G1, even p full TCR stim

High [IL-2] → ↑ sensitivity of ____ T cells to Fas mediated _____

• Ag-stim
• apoptosis

Possible that Ag-binding causes T cells to produce _____, while costim produces _____, so lack of costimulation causes apoptosis.

• pro-apoptotic proteins
• anti-apoptotic proteins

CD25+ is

• expressed in high levels by Treg
• the α chain of IL-2 receptor

Tregs produce

• IL-10 and TGF-β
• which block activation of T cells and macros

IL-2 first binds ____ of the IL-2 receptor with low affinity, then ___ contributes to binding and engages Jak3-STAT5-dependent signal transduction pathway

• IL-2Rα
• IL2/15Rβ

The ____ chain of the IL-2 receptor does not directly bind IL-2, but is required for high affinity binding and activation of signal transduction pathways

common γ

IL2Rα is newly induced by...

• naive T cell activation
• also causes upregulation of IL-2Rβ

Chronic T cell stim results in shedding of ___, which can be used as a marker of strong antigenic stim (e.g. acute graft rejection)

IL-2Rα

What are the roles of CTLA-4 and Treg inhibition in CD8+ cells?

UNCLEAR

Receptor editing is the process by which B cells in the marrow which interact with self- antigens change their...

• antigen specificity, by gene recombination of the light chain
• associates with OLD HEAVY CHAIN (no class ∆)

Ig light chain is made of either ___ or ___ chains, which in the mature human are in a ratio of ___.

• κ and λ
• 2:1

How is it determined that a B cell in the marrow that is highly self-binding is apoptosed or receptor edited?

unknown

Immature B cell first expresses light chain, resulting in sIgM with ____ still expressed.

• RAG-1, -2 (recombo activating genes)

If strong sIgM cross-linking does not occur, gene rearrangement ____ and RAG protein (↑/↓)

• gene rearrangement ceases
• RAG protein declines (but does not cease until maturity)

If there is strong sIgM cross-linking, development is ___ and RAG expression ____

• development is halted
• RAG expression continues @ level c/w light-gene chain rearrangement
• recombinase causes rearrangements

Receptor editing recombinase action

• fast, keeps going until not auto-reactive or VJ segments depleted
• If still auto-reactive cell apoptoses
• if κ exhausted, will try λ

T-independent antigens always yield Ig_ and form memory B cells with what frequency?

• M
• never

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