Team CDK
Daniel Packer
Rafael Rodriguez
Sahat Yalkabov
TCR Signaling Pathway
 TCR


T
(T cell receptor)
Molecule found on T Cells
Response for recognizing antigens on MHC
(Major Histocompatibility Complex)
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 Pnucleotide 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
Cumulative Distribution
1.00
0.90
0.80
Probability
0.70
pMHC(p~ag)=10
0.60
pMHC(p~ag)=100
0.50
pMHC(p~ag)=1000
0.40
pMHC(p~ag)=10k
0.30
pMHC(p~ag)=100k
0.20
No LCK Dephosphorilation
0.10
0.00
0.00
2.00
4.00
6.00
8.00
Time
10.00
12.00
14.00
Results
pMHC(p~ag)=10 Probability Distribution
18
16
14
Frequency
12
10
8
pMHC(p~ag)=10 Frequency
6
4
2
0
6-7
7-8
8-9 9-10 10-1111-1212-1313-1414-1515-1616-1717-18
Time
Results
pMHC(p~ag)=100 Probability Distribution
18
16
Frequency
14
12
10
8
Frequency
6
4
2
0
Time
Results
pMHC(p~ag)=1000 Probability Distribution
40
35
Frequency
30
25
20
Frequency
15
10
5
0
7-8
8-9
9-10
10-11
Time
11-12
12-13
Results
pMHC(p~ag)=10k
60.00
50.00
Frequency
40.00
30.00
Frequency
20.00
10.00
0.00
5-6
6-7
7-8
Time
8-9
Results
pMHC(p~ag)=100k
70
60
Frequency
50
40
30
Frequency
20
10
0
4-5
5-6
Time
6-7
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