Immuno-T Lymphocytes; Genetics Of Tcrs-T Cell Activation

Front 1

T cells: Key points

1) T cells recognize Ag when __________.

2) T cells recognize ______ Ag.

3)TCRs recognize Ag in association with _____.

4)TCRs are restricted to _____-MHC

Back 1

1)bound to the surface of cell
2)Protein
3)MHC
4)self

Front 2

H-2K and H-2d

Back 2

two different mouse class I MHC used to to demonstrate the fact that TCRs are restricted to self-MHC

Front 3

Exception to the rule that TCRs are restricted to self-MHC

Back 3

Alloreactivity

Front 4

Alloreactivity is when TCR recognize foreign MHC. Often times, this is the reason for graft rejection. T-cells recognize foreign MHC as an _________ without a Ag peptide. ~1-10% of T cells can recognize foreign MHC. In this case T cells are not _________. This Alloreactivity may be due to some kind of cross reactivity.

Back 4

ALLOANTIGEN/SELF-MHC RESTRICTED

Front 5

TCR structure

TCR is a Heterodimer with
ab or gd chains. It is very similar to the Fab portion of the B cell Ab.
Disulfide bonds and membrane anchors hold it together. Similar to B cell Ab there is a hInge region, _______ and constant regions, and
three ____(hypervariable regions. CDR3 seems to be the most important in contacting Ag

Back 5

VARIABLE/CDRs

Front 6

ab versus gd T cells

Back 6

-ab are the vast majority of CD3+ cells.
-They have much MORE TCR diversity.
-60% ARE CD4+ compared to <1% in gd
-ab are predominantly CD4+ where as gd are mostly CD8+
-CD4+ are restricted to MHC class II & CD8+ are restricted to MHC class I, where as in gd there are no restrictions.
-ab respond to the MHC-Ag peptide complex, whereas gd mostly just respond to phospholipid Ag

Front 7

In TCR genes the _____ locus is within the _____ locus, while the ______ and ______ loci are on the same chromosome but seperated.

Back 7

delta/alpha
beta/gamma

Front 8

TCR genes continued

alpha and gamma have a __ and __ (similar to Ig light chain)
beta and delta have a _, _, and _ (similar to Ig H chain)

Back 8

V/J
V/D/J

Front 9

TCR genes continued

Because the alpha locus is split by delta locus, a
productive rearrangement of ALPHA DELETES THE DELTA LOCUS the purpose of this is?

Back 9

So that you can’t have both a and d.

Front 10

Describe the C region of the TCR in relation to the IgH chains. Why are they different.

Back 10

They are much simpler than IgH chains.
They have no different biological activities of TCRs.

Front 11

TCR gene rearrangement occurs in the _______

Back 11

Thymus

Front 12

Placement of V & J regions in TCR gene rearrangement is directed by RSS (recombination signal sequences) which consists of a _______-_______-________. Spacer is a _______ sequence.

Back 12

HEPTAMER-SPACER-NONAMER
12 OR 23 BP

Front 13

In TCR gene rearrangement the ______ genes/enzymes are involved in cutting and pasting the V,D, J regions together

Back 13

RAG1/RAG2

Front 14

TCR gene rearrangement is a sequential process (as with Ig genes) the beta, gamma, and delta chain ____________.
If gamma delta have complete rearrangement first, then it will be a gamma delta T cell
If beta is first, it associates with a ______ goes to surface, and signals alpha rearrangement to begin.
In doing this, we delete the delta locus. The final result is that the T cell will be an ________.

Back 14

REARRANGE SIMULTANEOUSLY
PRE-T ALPHA
AB T CELL

Front 15

Allelic exclusion means

Back 15

for a given T cell, only one allele should be expressed at the same time

Front 16

Exception for allellic exclusion

Back 16

alpha locus not as tightly controlled so we CAN SEE 2 ALPHA ON THE SURFACE WITH THE SAME BETA CHAIN.

Most often, one TCR alpha beta is self-MHC restricted (i.e., functional)

Front 17

Diverisity of TCR - compare it to Ig diversity and explain.

Back 17

more diversity in TCR than in Ig(even though fewer V region genes) because there is a HIGHER NUMBER OF J REGIONS.

Front 18

Adding to the diversity of TCR is the fact that we can have alternative joining of ______ regions on the beta chain.

Back 18

D regions

Front 19

Diversity of T cells is due to

Back 19

1) Junctional flexibility

2) P nucleotides
(palindromic base additions)

3) N nucleotides (TDT enzyme addition)

these three thought to generate ~1013 possibilities (~107 for Abs)

Front 20

T cells are different from B cells in that you get NO SOMATIC HYPERMUTATION. True or False

Back 20

True

Front 21

Explain how diversity in TCR depends on contact with MHC

Back 21

There are fewer V region genes because have to contact limited number of MHC molecules. Specifically,
CDR1 and CDR2 INTERACT DIRECTLY WITH MHC so they are not very diverse.
There are higher number of J regions because these are the areas that have higher contact with Ag peptides (CDR3).

Front 22

TCR complex

Back 22

TCR and CD3 complex

Front 23

Describe CD3

Back 23

- INVARIANT CHAINS
- MOSTLY INTRACELLULAR
- intramembrane is NEGATIVELY CHARGED (to interact with positive charges of TCR)
-it has a SIGNALLING FUNCTION which utilizes ITAMs (immunoreceptor tryosine-based activation motifs)
- there are 3 ITAMS in the zeta homodimer and one on other CD3 polypeptides

-When binding Ag, conformational changes send signals to CD3 which then starts signaling cascade.

Front 24

T cell accessory molecules (co-receptors)

Back 24

CD4 contacts beta2 domain of class II
CD8 with alpha3 domain of class I

Front 25

importance of coreceptors

Back 25

Increase avidity of TCR with MHC and are needed for optimal signaling

E.g.,
100 TCR/Ag/MHC for activating T cell WITH CO-RECEPTOR

10,000 TCR/Ag/MHC for activating T cell WITHOUT CO-RECEPTOR(rarely would happen

Front 26

Adhesion molecues

Back 26

help hold T h/T c and Ag presenting cell/ Target cell together

Front 27

2nd signal in T cells

Back 27

CD28 cell(on T helpser cell)binds with B7 (on presenting cell)

Front 28

T cell maturation/differentiation

Back 28

progenitor T cells originate in bone marrow and move to thymus to be “educated”

Front 29

lack of thymus showed ________

Back 29

T cell defects

e.g., DiGeorge Syndrome

Front 30

T cell maturation/differentiation (cont.)

Earliest T cells express CD2 and are _______ or CD4-/CD8-

These cells go on to become either ab or gd T cells

Gene rearrangement begins in thymus

Back 30

DOUBLE NEGATIVE

Front 31

Describe the Pre-T cell receptor stage of T cell maturation/differentiation

Back 31

You have CD3, beta chain and pre-Talpha.
There is no CD4/CD8 expressed (double negative)

This stage is important in signaling to continue development (start alpha chain rearrangement)

Front 32

T cell maturation/differentiation (cont.)

Double negatives become ________(CD4+/CD8+)

These cells proliferate before alpha chain gene rearrangement. This increases diversity by putting same beta chains with different alpha.

Back 32

DOUBLE POSITIVES

Front 33

T cell maturation/differentiation (cont.)

After successful ab gene rearrangement, cells “tested” for binding
self reactive cells __________ (~98% of all T cells. Surviving cells become __________.

Back 33

DIE VIA APOPTOSIS/SINGLE POSITIVES

Front 34

Thymic selection consists of what two selection processes

Back 34

-positive selection
-negative selection

Front 35

describe positive selection

Back 35

select T cells that can interact with self-MHC

Front 36

describe negative selection

Back 36

T cells with high affinity for self-MHC alone &
T cells reactive to self-peptides die via apoptosis (cells not reacting are selected)

Front 37

which cells do the selecting

Back 37

thymic stromal cells because they have high levels of MHC I & II

Front 38

How long does the selection process take

Back 38

~3 weeks

Front 39

After which stage of selection does cell become CD4+ or CD8+

Back 39

After negative selection

Front 40

two-signal hypothesis

Back 40

In order to be activated, T cells need two signals

Front 41

What are the 2 signals for T cells

Back 41

Signal #1: TCR – Ag/MHC
Signal #2: CD28 / B7

Front 42

What is the significance of CTLA-4

Back 42

It is a 2nd signal that binds B7 with higher affinity than CD28 (on activated T cells)
It may send “suppression” signal

Front 43

What happens to T cells without 2 signals?

Back 43

T cells become anergic or apoptotic

Front 44

What are superantigens?

Back 44

They bind to a particular V Beta family and result in activation of a large population of T cells
There is a cytokine release.
Pathology is(inflammation, systemic cause shock)
apoptosis/anergy of stimulated T cells

e.g., are staphylococcal enterotoxins, Toxic-shock syndrome toxin, exfoliative-dermatitis toxin, streptococcal pyrogenic exotoxins, etc.

Front 45

T cell subsets

Back 45

ab and gd and NK1-T cells

Front 46

gd

Back 46

0.5-10% of all T cells
Do not recirculate
Express limited diversity
Skin/intestines

Front 47

NK1-T cells

Back 47

have rearranged TCRs (ab)
bind to CD1 MOLECULES(NOT CLASSICAL MHC) and lipids (Ag)
effector function similar to NK cells (cytotoxic)
secrete cytokines to attract Th cells
may function as a rapid response to invader (don’t need Ag processing of Ag

Front 48

ab T cell subsets

Back 48

CD4 (Th cells and Td cells)
& CD8 (Tc and Ts cells)

Front 49

Th0

Back 49

precursor helper cell (IL-2, IL-4)

Front 50

Th1

Back 50

IL-2, IFNg, and TNF-b (CMI)
(KNOW)

Front 51

Th2

Back 51

IL-4, IL-5, IL-6, and IL-10 (Ab)
(KNOW)

Front 52

Delayed type hypersensitive T cells (Tdth)

Back 52

CD4 cells that stimulate inflammation

Front 53

CD8 (Tc and Ts cells)

Back 53

CTLs
suppressor T cells