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Team CDK. Daniel Packer Rafael Rodriguez Sahat 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. - PowerPoint PPT Presentation
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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 14.000.000.100.200.300.400.500.600.700.800.901.00
Cumulative Distribution
pMHC(p~ag)=10pMHC(p~ag)=100pMHC(p~ag)=1000pMHC(p~ag)=10kpMHC(p~ag)=100kNo LCK Dephosphorilation
Time
Prob
abili
ty
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
02468
1012141618
pMHC(p~ag)=10 Probability Distribution
pMHC(p~ag)=10 Frequency
Time
Freq
uenc
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
18-19
19-20
20-21
21-22
22-23
23-24
02468
1012141618
pMHC(p~ag)=100 Probability Distri-bution
Frequency
Time
Freq
uenc
y
Results
7-8 8-9 9-10 10-11 11-12 12-1305
10152025303540
pMHC(p~ag)=1000 Probability Distri-bution
Frequency
Time
Freq
uenc
y
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
Freq
uenc
y
Results
4-5 5-6 6-70
10
20
30
40
50
60
70
pMHC(p~ag)=100k
Frequency
Time
Freq
uenc
y
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