Mimm 314: Effector Mediated Immunity To Pathogens

Front 1

What is one of the primary negative signals that hinder the co-stimulatoy pathway?

Back 1

CTLA-4

Front 2

When is CTLA-4 upregulated?

Back 2

After signalling o B7-CD28
CTLA-4 has 20x higher binding affinity for B7 and conveys a negative signal
->Post T-cell activation,as you inc time, inc # of CTLA-4 that upregulate and compete with upregulated B7 and outcompete CD28
(shift in preferential binding of B7 from CD28 to CTLA-4)

Front 3

What happens in CTLA-4 null mice?

Back 3

Lethal disorder involving massive lymphocyte proliferation

Front 4

Do we have auto-reactive T cells in the periphery?

Back 4

yes (since clonal deletion isn't perfect)
Ppl don't suffer from auto-immune disease because of mechanisms that control these cells. These mech include the CTLA-4 path
->CTLA-4 important to control auto-reactive T-cells and any activated cells

Front 5

What is ICOS?

Back 5

Inducible Co-Stimulators

Front 6

What is ICOS? What induces it?

Back 6

Another CD28-related molec
Induced on activated T-cells (NOT on naive T cells)

Front 7

Where does it bind?

Back 7

ICOS-ligand on:
activated dendritic cells
monocytes
B-cells

Front 8

What does ICOS stimulate?

Back 8

TH2 cytokine: IL10 (not IL2)

Front 9

What is the importance of IL10?

Back 9

Immunomodulatory
Immunosuppressive

Front 10

What are some other co-stimulatory molecules?

Back 10

OX40, CD30, CD27
**4-1BB (foundon CD8+ T-cells)

Front 11

What do CD8+ cells need for a good response?

Back 11

CD4+ T-cells
(if no CD4+ cells, CD8 cells will fatigue with time)

Front 12

What kind of help can CD8 get?

Back 12

CD4 activation of dendritic cells through CD40/CD40L path
IL-2: CD4 are very good producers of IL2
4-1BB/4-1BBL: CD4+ T cells activate APC cells (through co-stimulatory molec) after it was acitvated
->They would want to activate APC to keep immune response to go on by supporting Ag presentation and keeps B7 at a level of activity to sustained response

Front 13

What happens when activated APC upregulate 4-1BBL?

Back 13

4-1BBL can activate CD8+ cells in the form of IL-2 production, proliferation and differentiation

Front 14

What are 3 co-stimnulatory instances?

Back 14

CD28-B7
CD40-CD40L
4-1BB: 4-1BBL

Front 15

What is SMAC?

Back 15

Super Molecular Activating Complex

Front 16

What is SMAC for?

Back 16

Spatio-temporal for organization of T-cell surface ptns in immunological sunapse formation with APC

Front 17

What happens in early T-cell activation before signals have been given?

Back 17

T-cell and APC come in close proximity to each other
->The LFA molec tend to be in a dense core surrounded by a TCR and co-stimulatory molec & LFA is huge and T-cell is small: immature SMAC
-> Through actin cytoskeleton rearrangement, the dense core of the LFA is shifted to the outside and the TCR comes inside
->Once this inverion occurs, now a central SMAC as oppose to peripheral SMAC

Front 18

What happens in later T-cell activation?

Back 18

Mature SMAC:
-Peripheral SMAC (pSMAC): LFA-1:ICAM-1
-Central SMAC (cSMAC): TCR, CD4, CD28, MHC:peptide
Also true for CD8+ cells

Front 19

What does the TCR encounter?

Back 19

MHC/Ag peptide complex

Front 20

What do resting (naive) T cells express?

Back 20

L-selectin
TCR (down regulation in activated T-cellsif they get a good signal 1)
CD4
LFA-1 (upregulated on activated cells)

Front 21

What is expressed on activated T-cells?

Back 21

VLA-4 upregulated (v/ late Ag)
LFA-1 downregulated (don't want them to accumulate in the lymph node)
CD44: receptor for a ptn HA, part of extracellular matrix, is increased with activation and this activated T-cell s given another capacity to home and accumulate in inflmaed, non-lymphoid sites

Front 22

What are the 2 forms of CD45?

Back 22

RA and RO

Front 23

What forms of CD45 do the naive T-cells express?

Back 23

CD45RA+
CD45RO-

Front 24

Wha forms of CD45 do activated T-cells express?

Back 24

CD45RA-
CD45RO+

Front 25

What do you look for when you check for T-cell state?

Back 25

See shift i expression of RA/RO (if preference for RO, know this individual saw sufficient numbers of antigens)

Front 26

What is Sphingosine 1-phosphate (S1P)?

Back 26

Produced by mast cells and mononuclear phagocytes in immune organs, but not by T-cells
Secreted into T-cell corridors (LN) where it elicits and REGUATES T-cell mov't in thymus, LN and spleen and their chemotaxis in non-immune tissues

Front 27

Where des S1P bind?

Back 27

S1PR
Expressed in resting T-cells and NOT in activated T-cells

Front 28

What happens if S1PR are lost?

Back 28

Another que for developing activated T-cell to leave LN and enter inflamed non-lymphoid tissue

Front 29

What is signal 3 by APCs for dev'p T-cells?

Back 29

Immune activation of APC (through TLR, APC maturation or T-cell signals) condition this APC to now provide signal 3

Front 30

How does signal 3 come?

Back 30

Form of cocktail of inflammatory cytokines (IL-1/6/12) which can then act on a variety of cell typres, but primarily on T-cells to activate T-cell prolif and diff
->can stop CTLA-4 signalling form APC to T-cell

Front 31

What is the most efficient way of stimulating naive T-cells?

Back 31

Immature DC in peripheral tissues express many TLRs for common microbial products
->by LPS via TLR-4
->by detectin unmethylated CpG in DNA via TLR-9
-> by dsRNA

Front 32

What are the 3 classes of APC?

Back 32

Dendritic Cell
Macrophage
B cells

Front 33

Describe DC.

Back 33

Most efficient and specialized for Ag presenting (macropinocytosis)
Most efficient at stimulating naive T cells

Front 34

Which TLRs do immature DC in the peripheral tissues express?

Back 34

LPS via TLR-4
Unmethylated CpG via TLR-9

Front 35

Describe macrophages.

Back 35

Phagocytic cells
May present peptides from phagocytosed foreign material

Front 36

Describe B cells

Back 36

Specifically take up Ag which binds their BCR
May present onMHCII if induced to express costimulatory activity

Front 37

Describe IMMATURE DC

Back 37

Found in peripheral tissues
MHC I/II
LFA family, ICAM-1, DEC 205, DC-SIGN (both are important for Ag uptake and presentation)
Immature DC v/ good at uptake and presentation

Front 38

Describe mature DC

Back 38

Found in lymphoid tissue
MHC I/II
LFA family, DC-SIGN, loss of DEC 205, ICAM-2
B7-1 & 2
CCR7 (important for DC homing to cortical region of LN)
DC-chemokines (important for homing)
Maturation changes phenotype and function of DC

Front 39

What happens to the fct of the DC as it switches from immature to mature?

Back 39

Shifts capacites away from uptake and presentation towards co-stimulation

Front 40

What are the 2 classes on DC? Describe.

Back 40

Conventional DC: have all ptns from above
Plasmacytoid DC: different, do different thngs

Front 41

What does Plasmacytoid DC have?

Back 41

MHC II
B7
TLR-7/9
Particularly involved in INNATE sensing to TLRs
Also important in ANTI-VIRAL responses:largely due to its preferential capacity to secrete alpha/beta interferons
->what allows us to differentiate them

Front 42

What happens when you get a cut on the skin?

Back 42

Langerhan cells in the skin find the pathogen
Leave the skin and enther lymphatics and go to cortical LN to present Ag or transfer some of the Ag to LN resident DC
Initiates a certain level of AP and maturation, get B7 expression and activation of T-cell and division

Front 43

What dictates the passage from cut to cortical region of LN?

Back 43

Activation of certain signal (not random). Some of these paths:
-have immature DC which expressesits TLR/DEC205. With time, PAMP activates and signals TLRs and induces CCR7 expression and induces enhancing of expression of Ag by DC
-CCR7 directs migration of DC into lymphoid tissue and at teh same time, augment the expression of the necessary co-stimulation (maturation happens in cortical regions {T-cell zones} of the spleen)
-CCR7= example of homing mechanism that DC use to home from initial non-lymphoid site of inflammtion to the secondary lymphoid compartments to bring the potential Ag specific signal to incomin Ag-specific T-cell coming from its journey

Front 44

What influences the differentiation of Th cells during T-cell activation?

Back 44

Cytokine env't

Front 45

What T-cell develops if there are a lot of IL-12/IFN-gamma in the environment?

Back 45

Th1 CD4+ cells

Front 46

What type of T cell develops if there is a lot of IL-4 in the environment?

Back 46

Th2 CD4+

Front 47

What inhibits Th1 CD4+ growth?

Back 47

IL4/10

Front 48

What inhibits Th2 CD4 cells?

Back 48

IFN-gamma

Front 49

Why would Th1 CD4+ cells be favored?

Back 49

Favors CMI
IL-12 needed for differentiation
Produce: cytokines, IFN-gamma, IL-12

Front 50

What is the fct of Th1 CD4+ cells?

Back 50

Produces cytokies or ativatin CD8+ cytotoxicity
Delayed type hypersensitivity
APC activatin: infected macrophages
Stimulate B-cells to produce opsonizing IgG

Front 51

When is differentiation towards Th2 CD4+ favored?

Back 51

Favored in Humoral immunity
IL-4needed for differentiation
Produce: cytokines: IL-4/5/13

Front 52

What are the fcts of Th2?

Back 52

Provide essential help to Ag specific B-cells resulting in B-cell activation and IgA, IgE and IgG formations
Th2 responses often found in asthma and alergic responses due to prominent eosinophil responses

Front 53

If IFN-gamma is around, does that mean that every signal becomes Th1?

Back 53

No, have a bell curve for T-cell populations
always have some of each type of T-cells