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![Page 1: Statistical physics of T cell receptor selection and function Thesis committee meeting, 04/15/2009 Andrej Košmrlj Physics Department Massachusetts Institute.](https://reader035.fdocuments.us/reader035/viewer/2022062314/56649f445503460f94c6552f/html5/thumbnails/1.jpg)
Statistical physics of T cell receptor selection and
function
Thesis committee meeting, 04/15/2009
Andrej Košmrlj
Physics DepartmentMassachusetts Institute of Technology
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Andrej Košmrlj, 04/15/2009 2
QuickTime™ and aTIFF (LZW) decompressor
are needed to see this picture.
Immune system
Flexible system to combat diverse pathogens
Mis-regulation leads to autoimmune diseases
QuickTime™ and aGIF decompressor
are needed to see this picture.
Multiple Sclerosis Diabetes
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Andrej Košmrlj, 04/15/2009 3
Antigen presentation and recognition
APCs internally process self and foreign proteins, cut them to short peptides (8-15 aa) and present them on the surface
antigen recognition: strong binding of TCR to antigenic pMHC
self pMHC bind TCR more weakly
Antigen presenting cell T cell
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Andrej Košmrlj, 04/15/2009 4
T cell receptors
most T cell express distinct TCR - stochastic gene rearrangement process
TCR antigen recognition:degeneracy - each TCR can recognize many antigenic peptidesspecificity - TCR recognition of antigen is specific for single point amino acid mutations
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Andrej Košmrlj, 04/15/2009 5
Development in thymus
strongbinding
weakbinding
Negative selection deletes strongly binding autoimmune TCR
Positive selection results in weak binding of TCR to endogenous pMHC – implicated in survival, MHC restriction.
Palmer et al, Nature (2006)
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Andrej Košmrlj, 04/15/2009 6
Specificity of antigen recognition
• Specificity to antigenic peptide:
• Many peptides: mutations destroy activation – specific T-cells
• Single peptide: mutations don’t matter – cross-reactive T-cells
Huesby et al, Cell (2005)
P-1
P2
P3
P5
P-1
P2
P3
P5
Many self-peptides One self-peptide
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Andrej Košmrlj, 04/15/2009 7
Model
Surviving T cells: Eint > EN for all peptides; Eint < EP for at least one peptide
TCR-peptide contacts:
self peptides in thymus:
PNAS (2008)PRL (submitted)
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Andrej Košmrlj, 04/15/2009 8
Extreme value distribution
increasing M(self-peptides)
TCRs withweaker
amino acids
Selection condition:
Probability of TCR selection:
Properties of
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Andrej Košmrlj, 04/15/2009 9
Amino acid composition of selected TCRs
WEAKSTRONG
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Andrej Košmrlj, 04/15/2009 10
Selected TCRs are enriched withweak amino acids
WEAKSTRONG
Abhishek Jha
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Andrej Košmrlj, 04/15/2009 11
Frustration leads to specific TCR repertoire
One peptide
EN < E < EP
selected
E < EN
negatively selected
Many peptides
Solution: special class of sequences enriched with weak amino acids that distribute moderate interactions through the entire sequence
Optimizing interactions with one peptide leads to “bad” interactions with another
More hotspots – specific T cell repertoire
TCR
peptide
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Andrej Košmrlj, 04/15/2009 12
Recall specificity of antigen recognition
• Specificity to antigenic peptide:
• Many peptides: mutations destroy activation – specific T-cells
• Single peptide: mutations don’t matter – cross-reactive T-cells
Huesby et al, Cell (2005)
P-1
P2
P3
P5
P-1
P2
P3
P5
Many self-peptides One self-peptide
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Andrej Košmrlj, 04/15/2009 13
Specificity mirrors experiments
Hot spot: more than half the mutations of a peptide amino acid destroy reactivity
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Andrej Košmrlj, 04/15/2009 14
Increased number of moderately interacting contacts
B3K 506 TCRC57BL/6 derived
MHC + peptide specific
YAe62.8 TCRIAb-SP derived
MHC + peptide degenerate
Increased number of moderate interactions
Decreased number of strong interactions
Huesby et al, Nat. Immunol (2006)
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Andrej Košmrlj, 04/15/2009 15
TCR RECOGNITION ~ STATISTICAL SCAN OF A BAR CODE
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Andrej Košmrlj, 04/15/2009 16
Large N limit (1/2)
Selection condition:
Scaling in the large peptide (N) limit:
Statistical mechanics:
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Andrej Košmrlj, 04/15/2009 17
Large N limit (2/2)
Selection condition:
Hamiltonian minimization:
Amino acid composition of selected TCRs:STRONG AA
WEAK AA
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Andrej Košmrlj, 04/15/2009 18
Phase diagram
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Andrej Košmrlj, 04/15/2009 19
Selected TCRs are enriched withweak amino acids
WEAKSTRONG
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Andrej Košmrlj, 04/15/2009 20
Future project
HIV elite controllers (long term non-progressors) are associated with special MHC alleles (e.g. HLA B57). TCRs restricted by B57 allele are more cross-reactive - helps recognizing HIV mutants.
HLA B57 allele bind fewer peptide than most other alleles.
Our model: thymic selection with fewer self-peptides leads to more cross-reactive TCRs.
Connect thymic selection to viral dynamics model (Elizabeth Read) to explain differences in the acute phase of viral infection
HIV
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Acknowledgements
Arup K. Chakraborty
Mehran Kardar
Abhishek K. Jha
Elizabeth L. ReadThesis committee meeting, 04/15/2009
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Andrej Košmrlj, 04/15/2009 22
T cellInna
te I
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unit
yA
dapt
ive
Imm
unit
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QuickTime™ and aTIFF (LZW) decompressor
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Antigen presentation and recognition
QuickTime™ and aTIFF (LZW) decompressor
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dendritic cell
How does our immune system work ?
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Andrej Košmrlj, 04/15/2009 23
UNDERSTANDING ADAPTIVE IMMUNITY
Flexible system to combat diverse pathogens
Mis-regulation leads to autoimmune diseases
Multiple Sclerosis
The challenge: develop principlesprinciples that govern the emergence of an immune response or autoimmunity and design rulesdesign rules for therapies
Diabetes
Theory/computation Experiments
statistical mechanics genetics biochemistry imagingchemical kinetics
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Andrej Košmrlj, 04/15/2009 24
Model
Surviving T cells: E>EN for all peptides; E < EP for at least one peptide
TCR-peptide contacts:
self peptides in thymus:
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Andrej Košmrlj, 04/15/2009 25
Amino acid frequencies of recognized antigens
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Andrej Košmrlj, 04/15/2009 26
Distribution of single site contact energies
between reactive T cells and antigen
B3K 506 TCRC57BL/6 derived
MHC + peptide specific
YAe62.8 TCRIAb-SP derived
MHC + peptide degenerate
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Andrej Košmrlj, 04/15/2009 27
Distribution of single site contact energies
between reactive T cells and antigen
Increased number of moderate interactions
Decreased number of strong interactions
Selection with many peptides increases the number of moderate contacts between TCR and peptide amino acids
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Andrej Košmrlj, 04/15/2009 28
Recall hotspots in experiments
Hot spot: more than half the mutations of a peptide amino acid destroy reactivity
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Andrej Košmrlj, 04/15/2009 29
How long is peptide?
Human proteome P ≈107
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Andrej Košmrlj, 04/15/2009 30
TCR RECOGNITION IS LIKESCANNING A BAR CODE
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Andrej Košmrlj, 04/15/2009 31
Model
TCR pMHC
MHC peptide conserved variable
Miyazawa-Jernigan
Surviving T cells: E<EN for all peptides; E > EP for at least one peptide
Pairwise interactions
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Andrej Košmrlj, 04/15/2009 32
Fraction of selected T cells
Negative selection dominates
Positive selection dominates
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Andrej Košmrlj, 04/15/2009 33
Fraction of selected T cells
Negative selection dominates
Positive selection dominates