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Specificity, Diversity, and Self-tolerance of T-Cell Receptors by Thymic Selection

Specificity, Diversity, and Self-tolerance of T-Cell Receptors by Thymic Selection Andrej Kosmrlj Abhishek Jha Mehran Kardar Eric Huseby Arup K. Chakraborty.

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Specificity, Diversity, and Self-tolerance of T-Cell Receptors by Thymic Selection

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  1. Specificity, Diversity, and Self-tolerance of T-Cell Receptors by Thymic Selection Andrej Kosmrlj Abhishek Jha Mehran Kardar Eric Huseby Arup K. Chakraborty

  2. T Cells orchestrate adaptive immunity, via Receptors that recognize short peptides from pathogen proteins T Cell TCR pMHC Antigen Presenting Cell

  3. T Cells Receptors (TCRs) must be: Self-tolerant,i.e. weakly binding to endogenous pMHC, to avoid autoimmune diseases, e.g. Multiple sclerosis, diabetes, … Diverse,to recognize an evolving landscape of pathogens. Specific/degenerate,to lock on specific pathogen, and tolerate its mutants. pMHC

  4. What is the shortest peptide length that ensures self-tolerance? Number of distinct human peptides n*= 5.3 Length of peptide, n In principle all human peptides can be recognized from sequences of length 5-6. What is the physical mechanism that enables recognition of self-peptides?

  5. T Cells are designed in the Thymus where a diverse repertoire of thymocytes is culled by encounters with self pMHC. Positive selection TCR must bind sufficiently strongly to at least one self pMHC (implicated in MHC restriction, and sensitivity). Negative selection TCR must not bind any self pMHC too strongly (deleting autoimmune TCR).

  6. Model for TCR selection in the Thymus conserved variable TCR {L} Miyazawa-Jernigan pMHC {J} peptide MHC Surviving T cells: E > EPfor at least one peptide, E<EN for all peptides + ✓ E --

  7. Diversity The selection process biases the composition of amino-acids in mature TCRs: Negative selection leads to a slight preference for weak amino-acids.

  8. STRONG WEAK Frequency of TCR amino-acids from known TCR-pMHC crystal structures (Thermophiles used for ordering, Shakhnovich et al., PLOS, 2007) (MJ used for ordering) Frequency in TCR/Frequency inproteome

  9. Specificity Eric S. Huseby et al, Cell (2005); Nature Immunol. (2007), compared the T cells of normal mice, with mice genetically engineered to present only one type of peptide in their thymus. T cells selected in the thymus are challenged with an antigenic peptide, and reactive T cells identified. Does a reactive T cell remain reactive upon mutating the peptide’s amino acids? If mutations to an amino acid destroy reactivity with at least half the T cells, the amino-acid is labeled a “hot spot”. • Main results: • Single peptide selection: few hot spots – cross-reactive T cells • Many peptide selection: many hot spots – specific T cells

  10. Specificity to antigen peptide: • Single peptide: mutations don’t matter – cross-reactive T-cells • Many peptides: mutations destroy reactivity – specific T-cells

  11. Numerical results for hot-spots† mirror the experimental situation frequency †Hot-spots are defined as locations along the sequence, where mutations of a peptide amino acid destroy reactivity with more than half the reactive T cells

  12. Frustration during negative selection constrains TCR sequences One peptide Ep < E < EN selected

  13. Frustration during negative selection constrains TCR sequences One peptide selected

  14. Frustration during negative selection constrains TCR sequences One peptide selected Many peptides E > EN negatively selected Optimizing interactions with one peptide can lead to “bad” interactions with another – FRUSTRATION. Positive selection does not involve frustration.

  15. Specificity, Diversity, and Self-tolerance of T-Cell Receptors by Thymic Selection Andrej Kosmrlj Abhishek Jha Mehran Kardar Eric Huseby Arup K. Chakraborty

  16. Frustration during negative selection constrains TCR sequences

  17. Frustration during negative selection constrains TCR sequences Solution: Prob. that a TCR is selected negative selection lead to choice of TCR amino acids which minimize interactions with other amino acids in En peptides.

  18. COMPUTATIONAL RESULTS Frequency in TCR/Frequency in proteome strong weak Robust to variations in potential

  19. AMINO ACID FREQUENCIES FROM TCR-PMHC CRYSTAL STRUCTURES (Thermophiles used for ordering, Shakhnovich et al., PLOS, 2007) STRONG WEAK Frequency in TCR/Frequency in proteome

  20. Distribution of single site contact energies for selected T cell-antigenic peptide interactions Increased number of moderate interactions Decreased number of strong interactions strong weak Selection with many peptides: TCR sequences contain amino acids that interact with Ag peptide amino acids moderately

  21. Modest interactions lead to specificity: Weak multivalent interactions stabilize the interface, making each interaction important for recognition Selection against one peptide – only few important sites

  22. How much Free Energy of Binding is due to each amino acid for specific versus degenerate TCRs? B3K 506 TCR C57BL/6 derived MHC + peptide specific YAe62.8 TCR IAb-SP derived MHC + peptide degenerate

  23. TCR sequences are specific, but diverse One type of sequences are selected – ones with a predominance of weak amino acids + + + - + + + + - - + + + - + + TCR sequences are cross-reactive (degerate) Several antigenic peptides composed of sufficient number of strong amino acids can interact productively with a given TCR

  24. ADAPTIVE IMMUNITY IN HEALTH AND DISEASE Mis-regulation leads to autoimmune diseases Flexible system to combat diverse pathogens Multiple Sclerosis Diabetes The challenge: develop principles that govern the emergence of an immune response or autoimmunity and design rules for therapies The problem: underlying mechanisms characterized by cooperative dynamic processes involving many components and a spectrum of length/time scales

  25. T CELLS RECOGNIZE SHORT PEPTIDES DERIVED FROM PATHOGEN’S PROTEINS

  26. Extraordinary Sensitivity of T cells for Antigen mixture of self (En) and antigenic (Ag/agonist) As few as 3 Ag molecules in a sea of 30,000 En can activate a T cell (Nature, 2002) How does this exquisite sensory apparatus work without frequent “noise”-induced autoimmune responses? T cell sensitivity to Ag pMHC is predicated upon degenerate weak interactions with En pMHC. With Mark Davis’ lab. (Nature Imm., 2004; Nature, 2005; PNAS, 2007; unpublished)

  27. Ec-EN is large (conserved TCR-MHC interactions are very weak) Small gap Ec Ep EN Large gap Ep Ec EN INFLUENCE OF PARAMETERS IN MODEL Parameters: Ec, EN, Ep Positive selection limiting; These are the TCRs that are not positively selected (MHC restriction); one or many types of peptides lead to similar consequences

  28. Ec-EN is small (conserved TCR-MHC interactions are very strong) Small gap Ec Ep EN Large gap Ep Ec EN Negative selection very easy; For many types of peptides almost all T cells are negatively selected.

  29. Life Sciences Physical Sciences Engineering sciences An approach at the intersection of disciplines Theory/computation Experiments statistical physics genetics biochemistry imaging chemical kinetics

  30. THYMIC SELECTION THRESHOLDS Palmer lab, Nature (2006) weakest strongest Sharp boundary separates positive and negative selectors MOLECULAR MECHANISM (w/A.Weiss’ lab.)

  31. A MEMBRANE-PROXIMAL SIGNALING MODULE IMPLICATED(with Jayajit Das, Ashok Prasad; Jeroen Roose, Art Weiss@UCSF) A positive feedback loop results in digital signaling and a sharp threshold Cell, PNAS, in review (2008)

  32. SHORT PEPTIDES ARE SUFFICIENT TO RENDER T CELLS SELF-TOLERANT AND REACTIVE TO FOREIGN

  33. SHORT PEPTIDES ARE SUFFICIENT TO RENDER T CELLS SELF-TOLERANT AND REACTIVE TO FOREIGN Longer peptides (length = n) will enable sampling of more distinct peptides ~20n

  34. SHORT PEPTIDES ARE SUFFICIENT TO RENDER T CELLS SELF-TOLERANT AND REACTIVE TO FOREIGN n=5.3 Condition for plateau: Total # of unique peptides of size, n Total size of human proteins

  35. ACKNOWLEDGMENTS Group members: J. Das, A. Prasad, M. Artomov, C. Govern, H. Zheng, A. Jha, J. Locasale, K. Fowler, M. Wolfson, A. Prabhakar, M. Yang, F. Liang, A. Kosmrlj. Collaborators:M. Davis, A. Shaw,P. Allen, A. Weiss, J. Roose, H. Ploegh M. Dustin, M. Kardar, A Perelson, J. Chen, U. von Andrian, H. Eisen, V. Kuchroo, E. Palmer, E. Huseby. Funding:NIH Immune Response Consortium

  36. Is there an optimal peptide length? Most TCR negatively selected

  37. IMPORTANCE OF PEPTIDE IN ALLO REACTIVITY DEPENDS UPON THE ALLO MHC Modest change Bigger change

  38. Theoretical models and experimental tests(Nature Imm. (2004); Nature (2005); PNAS (2007); unpublished) T cell sensitivity to Ag pMHC is predicated upon degenerate weak interactions with En pMHC that are tuned in the thymus.

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