Team CDK Daniel Packer Rafael Rodriguez Sahat Yalkabov.

Team CDKDaniel PackerRafael RodriguezSahat Yalkabov

TCR Signaling Pathway TCR (T cell receptor)

Molecule found on T Cells Response for recognizing antigens on

MHC (Major Histocompatibility Complex) T cell is activated when TCR engages

with antigen

T cells Belong to white blood cells group called

lymphocytes Play central role in immunity

Distinguished from other cells by the presence of TCR on its surface

Named T cells because they mature in thymus

Electron micrograph of T cell

T cell formation

CD8+ and CD4+ T cells CD8+ (Cytotoxic T cells)

Destroy virally infected cells and tumor cells Transplant rejection Recognize targets by binding to antigens

associated with MHC class I Present on ~99.9% of the cells in the body

Deactivated to anergic (inactive) state with the help of molecules secreted by the T-reg cells To prevent autoimmune diseases

CD8+ and CD4+ T cells CD4+ (Helper T cells)

Assist white blood cells with immunologic processes, as well as activation of cytotoxic T cells

Activates with peptide antigens from MHC class II molecules (pMHC) Expressed on the surface of APCs

When activated, divide rapidly and secrete small proteins called cytokines Regulate or assist active immune response

MHC Cell surface molecule Mediate interactions between white blood cells

and other immune cells or the body cells Determines compatibility of organ transplants Measures the susceptibility to autoimmune

diseases In humans, MHC also called HLA (human

leukocyte antigen) MHC region occurs on chromosome 6

Structure of TCR Member of immunoglobulin superfamily Consists of 2 halves:

Alpha/Beta and Gamma/Delta fragments Structure similar to immunoglobulin Fab

fragments

Generation of TCR 1/2 Alpha/Gamma chain - generated by VJ

recombination Beta/Delta chain – generated by V(D)J

recombination Intersection corresponds to CDR3 region

Important for antigen-MHC recognition

Generation of TCR 2/2 Involves random joining of gene

segments to complete TCR chain Unique combinations of segments, as

well as palindromic and random N- and P- nucleotide additions accounts for great diversity

T cell activation 1/2 TCR complex identifies specific bound antigen

and elicits a distinct response The mechanism by which T cells evoke response is

called T cell activation The most common mechanism for activation is

via phos./dephos. by proten kinases. TCR associated reactions kinases:

Lck Fyn CD45 Zap70

T cell activation 2/2 pMHC(agonist)

Interacts even at low concentrations

pMHC(endogenous) Weak interactions / No effect

Target molecule: ERK Extracellular signal-regulated kinases Involved in regulation of meiosis,

mitosis, and postmitotic. Activates on:

Growth factors, cytokines, virus infection, transforming agents, carcinogens.

Results

2.00 4.00 6.00 8.00 10.00 12.00 14.000.00

0.10

0.20

0.30

0.40

0.50

0.60

0.70

0.80

0.90

1.00

Cumulative Distribution

pMHC(p~ag)=10pMHC(p~ag)=100pMHC(p~ag)=1000pMHC(p~ag)=10kpMHC(p~ag)=100kNo LCK Dephosphorilation

Time

Pro

babilit

y

Results

6-7 7-8 8-9 9-10 10-11

11-12

12-13

13-14

14-15

15-16

16-17

17-18

0

2

4

6

8

10

12

14

16

18

pMHC(p~ag)=10 Probability Distribution

pMHC(p~ag)=10 Frequency

Time

Fre

quency

Results

6-7

7-8

8-9

9-10

10-1

1

11-1

2

12-1

3

13-1

4

14-1

5

15-1

6

16-1

7

17-1

8

18-1

9

19-2

0

20-2

1

21-2

2

22-2

3

23-2

40

2

4

6

8

10

12

14

16

18

pMHC(p~ag)=100 Probability Distri-bution

Frequency

Time

Fre

quency

Results

7-8 8-9 9-10 10-11 11-12 12-130

5

10

15

20

25

30

35

40

pMHC(p~ag)=1000 Probability Distri-bution

Frequency

Time

Fre

quency

Results

5-6 6-7 7-8 8-90.00

10.00

20.00

30.00

40.00

50.00

60.00

pMHC(p~ag)=10k

Frequency

Time

Fre

quency

Results

4-5 5-6 6-70

10

20

30

40

50

60

70

pMHC(p~ag)=100k

Frequency

Time

Fre

quency

Conclusion pMHC(endogenous) had little to no effect on

the activation times of ERK pMHC(agonist) had a very noticeable effect on

the activation times of ERK ERK concentration starts around 202,000 and

tops out at 296,000 The activation times of ERK depend on

pMHC(agonist) concentrations The greater pMHC concentration, quicker are the

activation times and smaller the time distribution