αβ T cell receptors as predictors of health and disease

The diversity of antigen receptors and the specificity it underlies are the hallmarks of the cellular arm of the adaptive immune system. T and B lymphocytes are indeed truly unique in their ability to generate receptors capable of recognizing virtually any pathogen. It has been known for several decades that T lymphocytes recognize short peptides derived from degraded proteins presented by major histocompatibility complex (MHC) molecules at the cell surface. Interaction between peptide-MHC (pMHC) and the T cell receptor (TCR) is central to both thymic selection and peripheral antigen recognition. It is widely assumed that TCR diversity is required, or at least highly desirable, to provide sufficient immune coverage. However, a number of immune responses are associated with the selection of predictable, narrow, or skewed repertoires and public TCR chains. Here, we summarize the current knowledge on the formation of the TCR repertoire and its maintenance in health and disease. We also outline the various molecular mechanisms that govern the composition of the pre-selection, naive and antigen-specific TCR repertoires. Finally, we suggest that with the development of high-throughput sequencing, common TCR ‘signatures’ raised against specific antigens could provide important diagnostic biomarkers and surrogate predictors of disease onset, progression and outcome.Cellular & Molecular Immunology advance online publication, 26 January 2015; doi:10.1038/cmi.2014.134

[1]  C. Carlson,et al.  Overlap and Effective Size of the Human CD8+ T Cell Receptor Repertoire , 2010, Science Translational Medicine.

[2]  Keiji Tanaka,et al.  Thymoproteasome shapes immunocompetent repertoire of CD8+ T cells. , 2010, Immunity.

[3]  Pratip K. Chattopadhyay,et al.  Public clonotype usage identifies protective Gag-specific CD8+ T cell responses in SIV infection , 2009, The Journal of experimental medicine.

[4]  S. Tonegawa,et al.  Peptide contributes to the specificity of positive selection of CD8+ T cells in the thymus , 1993, Cell.

[5]  L. Wedderburn,et al.  Immunological characteristics and T-cell receptor clonal diversity in children with systemic juvenile idiopathic arthritis undergoing T-cell-depleted autologous stem cell transplantation , 2014, Immunology.

[6]  L. Wilkinson.  Immunity , 1891, The Lancet.

[7]  S. Jameson,et al.  Thymoproteasome subunit-β5T generates peptide-MHC complexes specialized for positive selection , 2013, Proceedings of the National Academy of Sciences.

[8]  Todd M. Allen,et al.  TCR clonotypes modulate the protective effect of HLA class I molecules in HIV-1 infection , 2012, Nature Immunology.

[9]  Random T-Cell Receptor Recruitment in Human Immunodeficiency Virus Type 1 (HIV-1)-Specific CD8+ T Cells from Genetically Identical Twins Infected with the Same HIV-1 Strain , 2007, Journal of Virology.

[10]  Elizabeth Simpson,et al.  Public T Cell Receptor β-Chains Are Not Advantaged during Positive Selection1 , 2008, The Journal of Immunology.

[11]  Richard A. Olshen,et al.  Diversity and clonal selection in the human T-cell repertoire , 2014, Proceedings of the National Academy of Sciences.

[12]  D. Raulet.  The structure, function, and molecular genetics of the gamma/delta T cell receptor. , 1989, Annual review of immunology.

[13]  U. Utz,et al.  Skewed T-cell receptor repertoire in genetically identical twins correlates with multiple sclerosis , 1993, Nature.

[14]  B. Rocha,et al.  Homeostasis of T cell numbers: from thymus production to peripheral compartmentalization and the indexation of regulatory T cells. , 2005, Seminars in immunology.

[15]  M. Davenport,et al.  Evolution of the Antigen-Specific CD8+ TCR Repertoire across the Life Span: Evidence for Clonal Homogenization of the Old TCR Repertoire , 2011, The Journal of Immunology.

[16]  D. Kabelitz,et al.  TCR trans-Rearrangements: Biological Significance in Antigen Recognition vs the Role as Lymphoma Biomarker , 2006, The Journal of Immunology.

[17]  Brian J. Stevenson,et al.  Highly diverse TCRα chain repertoire of pre‐immune CD8+ T cells reveals new insights in gene recombination , 2012, The EMBO journal.

[18]  V. Stewart,et al.  RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement , 1992, Cell.

[19]  I. Messaoudi,et al.  Direct Link Between mhc Polymorphism, T Cell Avidity, and Diversity in Immune Defense , 2002, Science.

[20]  K. Suhre,et al.  High TCR diversity ensures optimal function andhomeostasis of Foxp3+ regulatory Tcells , 2011, European journal of immunology.

[21]  E. Simpson,et al.  Public T cell receptor beta-chains are not advantaged during positive selection. , 2008, Journal of immunology.

[22]  Andrew K. Sewell,et al.  Why must T cells be cross-reactive? , 2012, Nature Reviews Immunology.

[23]  M. Blackman,et al.  The narrowing of the CD8 T cell repertoire in old age. , 2011, Current opinion in immunology.

[24]  Katherine K. Matthews,et al.  β-Cell–Specific CD8 T Cell Phenotype in Type 1 Diabetes Reflects Chronic Autoantigen Exposure , 2014, Diabetes.

[25]  Andrew K. Sewell,et al.  Genetic and Structural Basis for Selection of a Ubiquitous T Cell Receptor Deployed in Epstein-Barr Virus Infection , 2010, PLoS pathogens.

[26]  A. Feeney,et al.  Deep Sequencing of the Murine Igh Repertoire Reveals Complex Regulation of Nonrandom V Gene Rearrangement Frequencies , 2013, The Journal of Immunology.

[27]  K. M. Partington,et al.  Differential effects of peptide diversity and stromal cell type in positive and negative selection in the thymus. , 1998, Journal of immunology.

[28]  M. Salvetti,et al.  Characterization of CD8+ T cell repertoire in identical twins discordant and concordant for multiple sclerosis , 2007, Journal of leukocyte biology.

[29]  E. Brooks,et al.  V(D)J recombination defects in lymphocytes due to RAG mutations: severe immunodeficiency with a spectrum of clinical presentations. , 2001, Blood.

[30]  Mark M. Davis,et al.  T-cell antigen receptor genes and T-cell recognition , 1988, Nature.

[31]  M. Davey,et al.  T cell receptor V beta gene expression in monozygotic twins. Discordance in CD8 subset and in disease states. , 1994, Journal of immunology.

[32]  Yuanyue Li,et al.  Recombinatorial Biases and Convergent Recombination Determine Interindividual TCRβ Sharing in Murine Thymocytes , 2012, The Journal of Immunology.

[33]  M. Bevan,et al.  Selecting and maintaining a diverse T-cell repertoire , 1999, Nature.

[34]  F. Cucca,et al.  T-cell receptor repertoire analysis in monozygotic twins concordant and discordant for type 1 diabetes. , 2012, Immunobiology.

[35]  M. Bevan,et al.  Selecting and maintaining a diverse T-cell repertoire , 1999, Nature.

[36]  T. Sumida,et al.  T-Lymphocyte–Receptor Repertoire of Infiltrating T Lymphocytes Into NOD Mouse Pancreas , 1991, Diabetes.

[37]  I. Messaoudi,et al.  MHC Polymorphism Can Enrich the T Cell Repertoire of the Species by Shifts in Intrathymic Selection , 2000, The Journal of Immunology.

[38]  M. Busslinger,et al.  Control of antigen receptor diversity through spatial regulation of V(D)J recombination. , 2013, Cold Spring Harbor symposia on quantitative biology.

[39]  M. Bevan,et al.  Positive selection of CD8+ T cells induced by major histocompatibility complex binding peptides in fetal thymic organ culture , 1993, The Journal of experimental medicine.

[40]  Stanford Peng.  The Thymus , 1965, The Australian nurses' journal. Royal Australian Nursing Federation.

[41]  Brian J. Stevenson,et al.  Highly diverse TCRα chain repertoire of pre‐immune CD8+ T cells reveals new insights in gene recombination , 2012, The EMBO journal.

[42]  C. Edwards,et al.  Naturally Occurring ERAP1 Haplotypes Encode Functionally Distinct Alleles with Fine Substrate Specificity , 2013, The Journal of Immunology.

[43]  A. Lesk,et al.  The outline structure of the T‐cell alpha beta receptor. , 1988, The EMBO journal.

[44]  Frode Vartdal,et al.  High‐throughput sequencing of TCR repertoires in multiple sclerosis reveals intrathecal enrichment of EBV‐reactive CD8+ T cells , 2014, European journal of immunology.

[45]  M. Krangel,et al.  Accessibility control of T cell receptor gene rearrangement in developing thymocytes , 2000, Immunologic research.

[46]  A. Casrouge,et al.  A Direct Estimate of the Human αβ T Cell Receptor Diversity , 1999 .

[47]  J. Dyson,et al.  Reduced Regulatory T Cell Diversity in NOD Mice Is Linked to Early Events in the Thymus , 2014, The Journal of Immunology.

[48]  J. V. van Dongen,et al.  Reviewing Omenn syndrome , 2001, European Journal of Pediatrics.

[49]  A. Fischer,et al.  Identical mutations in RAG1 or RAG2 genes leading to defective V(D)J recombinase activity can cause either T-B-severe combined immune deficiency or Omenn syndrome. , 2001, Blood.

[50]  J Nikolić-Zugić,et al.  Role of self-peptides in positively selecting the T-cell repertoire. , 1990 .

[51]  M. Thomsen,et al.  Corecognition of HLA-A1 and HLA-DPw3 by a human CD4+ alloreactive T lymphocyte clone , 1990, The Journal of experimental medicine.

[52]  Ellen V. Rothenberg,et al.  Developmental gene networks: a triathlon on the course to T cell identity , 2014, Nature Reviews Immunology.

[53]  H. von Boehmer,et al.  The thymus selects the useful, neglects the useless and destroys the harmful. , 1989, Immunology today.

[54]  F. Alt,et al.  Developmentally controlled and tissue-specific expression of unrearranged VH gene segments , 1985, Cell.

[55]  Mikhail Shugay,et al.  Distinctive properties of identical twins' TCR repertoires revealed by high-throughput sequencing , 2014, Proceedings of the National Academy of Sciences.

[56]  M. Bevan,et al.  In thymic selection, peptide diversity gives and takes away. , 1997, Immunity.

[57]  S. Jameson,et al.  Qualitative and quantitative differences in T cell receptor binding of agonist and antagonist ligands. , 1999, Immunity.

[58]  A. Singer,et al.  MHC restriction is imposed on a diverse T cell receptor repertoire by CD4 and CD8 co-receptors during thymic selection. , 2012, Trends in immunology.

[59]  James McCluskey,et al.  T cell antigen receptor recognition of antigen-presenting molecules. , 2015, Annual review of immunology.

[60]  M. Bevan,et al.  Role of self-peptides in positively selecting the T-cell repertoire , 1990, Nature.

[61]  L. Hood,et al.  Characterization of the T cell receptor repertoire causing collagen arthritis in mice , 1993, The Journal of experimental medicine.

[62]  P. Marrack,et al.  The major histocompatibility complex-restricted antigen receptor on T cells in mouse and man: Identification of constant and variable peptides , 1983, Cell.

[63]  Andres Jerez,et al.  Deep sequencing of the T-cell receptor repertoire in CD8+ T-large granular lymphocyte leukemia identifies signature landscapes. , 2013, Blood.