T cell response

Question 0

Positive selection

Answer 0

After TCR rearrangement and expression
TCR binds weakly to either MHC I or MHC II + self peptide ->
TCR-mediated survival signal (Ras MED, ERK)
If no TCR:MHC binding -> death by neglect

In cortex, mediated by thymic epithelial cells

Question 1

Overview of T cell maturity

Answer 1

Bone marrow -blood> thymus (not thyroid)
Begin expressing CD4, CD8, TCR
Positive and negative selection in thyroid -> most die
“Maturity” and type (CD4 and CD8) determined by TCR

Leave thymus as mature (functional TCR) but naive (haven’t seen their MHC:peptide match)

Question 2

CD4 vs CD8 determination

Answer 2

All thymocytes begin as “double positive” (CD4+, CD8+)
TCR rearrangement -> expression -> selection

If TCR:MHC I binds -> CD4 stops expression -> CD8+ cell
If TCR:MHC II binds -> CD8 stops expression -> CD4+ cell

Question 3

Negative selection

Answer 3

In medulla of thymus
Higher expression of TCRs
If TCR:MHC binding is too tight (high affinity)-> apoptosis
(might react against self-peptide)
AIRE = autoimmune regulator - thymic epithelium expresses ALL self peptides (not just thymus genes) on lots of MHC’s
- tests tolerance to all tissues of the body
Imperfect/leaky process -> peripheral tolerance silences

Question 4

Positive vs negative selection

Answer 4

Positive - 
- slow activation
- RasMED-ERK signals
- perfect process (unless cyclosporin is used...)
Negative -
- rapid apoptosis pathway
- many (>70) signals
- imperfect - MHC may not be exposed to all antigens

Question 5

T cell tolerance

Answer 5

Central tolerance = negative selection in thymus
- AIRE (autoimmune regulator) - thymic expression of all self peptides -> should “see” and test all peptides but not perfect

Peripheral tolerance - in tissue

• anergy of T cell if it binds MHC+peptide without costimulatory signals (B7 from APC indicating pathogen or inflammation)
• can also be from CTLA-4 binding to B7

Question 6

T cell-mediated suppression

Answer 6

Body only wants minimum response necessary to get rid of threat
Prevent autoimmunity, end response, mediate response

Have strong MHC binding (barely sneak through negative selection)
Express CD4, CD25 (IL-2 receptor), FoxP3
Function
- contact dependent
- release anti-inflammatory cytokines - IL-10, TNF-beta

Question 7

T cell activation

Answer 7

TCR:MHC+peptide match + costimulatory signal (ex CD28 on APC) -> binding and sharing of multiple cytokine signals

• > autocrine growth factors (IL-2 and CD40/IL-2 receptor)
• > cytokines, membrane proteins (CD 154, CTLA-4)
• > migration and effector function

Question 8

Timeline of T-cell response

Answer 8

Activation -> exponential expansion -> effector

• > contraction via Treg, apoptosis
• > memory allows faster, stronger exponential expansion on second exposure

Question 9

Memory T cells

Answer 9

Effector memory - remains in tissue either short or long term
- fast effectors - don’t need APC costimulation for activation
- can’t proliferate response
Central memory - circulating
- require new activation by MHC and APC costimulation
- proliferate -> new wave of response

Question 10

Cytotoxic T cells

Answer 10

aka activated CD8+
Respond to intracellular pathogens (ie viruses) via MHC I pathway
- activated by APC, then can recognize any cell expressing MHC I + viral protein

• granules -> perforin (disrupt membrane), granzymes (-> apoptosis)
• membrane Fas-L -> Fas receptor -> apoptosis
• interferon gamma -> impairs viral replication
• TNF-alpha

Question 11

Helper T subtypes

Answer 11

All CD4 begin as “Th0” -> cytokines get more restricted

Th1 - intracellular pathogen -> inflammation
- induced by IL-12, produce INF-g and TNF
Th2 - extracellular pathogens -> help B cell response
- induced by IL-4, produce IL-4, IL-5, IL-13
Th17 - new? autoimmunity? bacteria?
- makes IL-17

Question 12

Th1 mechanisms

Answer 12

Inflammatory -> intracellular pathogens (via macrophages)

Cytokines -> macrophages to infection site, produce O2 species, B7, MHC, cytokines
TNF-a -> activate macrophages, endothelial adhesion
IFN-g -> activate macrophages, inhibit Th2, promote Th1
GM-CSF and IL-3 -> more macrophages produced and released

Question 13

Macrophage function

Answer 13

Requires Th1 cytokines!

Endocytose -> need stimulation to produce reactive O2 species, enzymes
Ex: respiratory infection -> phagocytosis -> IFN-g suppresses viral replication -> TNF-a helps lymphocytes infiltrate -> induce O2 species

Can be inhibited by Th2! (IL-10, IL-4)

Question 14

Th2 function

Answer 14

Activate B cells -> extracellular

Cytokines (IL-4) + surface molecules (CD40 ligand) ->
B cells produce antibodies, higher affinity, class switching
-> IgE -> mast cell via Fc receptor -antigen> degranulate -> release IL-4 -> more Th2…(positive feedback)

IL-5 -> eosinophil production -> helminths, asthma…

Question 15

Lymphocyte circulation

Answer 15

Maximize encounters between lymphocytes and APC’s
Ex: dendritic cell activated -> lymph node
-> T cell circulates -> contacts dendritic cell -> primed

This is the purpose of secondary lymph organs!
T cells that don’t find MHC:antigen match die and new diverse pool made

Question 16

T cell migration

Answer 16

Programmed for destination: integrins and selectins
-> adhesion with endothelial ligands (ICAM, VCAM, etc) -> slow down -> local chemokines -> extravasion

Ex: naive express L-selectin -> lymph node -> local chemokines direct through node

Question 17

MALT

Answer 17

Mucosal-associated lymphoid tissue

T cells can migrate between different mucosal surfaces!
Still directed by local chemokines