A Mechanism for TCR Sharing between T Cell Subsets and Individuals Revealed by Pyrosequencing

The human naive T cell repertoire is the repository of a vast array of TCRs. However, the factors that shape their hierarchical distribution and relationship with the memory repertoire remain poorly understood. In this study, we used polychromatic flow cytometry to isolate highly pure memory and naive CD8+ T cells, stringently defined with multiple phenotypic markers, and used deep sequencing to characterize corresponding portions of their respective TCR repertoires from four individuals. The extent of interindividual TCR sharing and the overlap between the memory and naive compartments within individuals were determined by TCR clonotype frequencies, such that higher-frequency clonotypes were more commonly shared between compartments and individuals. TCR clonotype frequencies were, in turn, predicted by the efficiency of their production during V(D)J recombination. Thus, convergent recombination shapes the TCR repertoire of the memory and naive T cell pools, as well as their interrelationship within and between individuals.

[1]  R. Holt,et al.  Profiling the T-cell receptor beta-chain repertoire by massively parallel sequencing. , 2009, Genome research.

[2]  D. Price,et al.  Quantum dot semiconductor nanocrystals for immunophenotyping by polychromatic flow cytometry , 2006, Nature Medicine.

[3]  Abigail Wacher,et al.  Comprehensive assessment of T-cell receptor beta-chain diversity in alphabeta T cells. , 2009, Blood.

[4]  E. Myers,et al.  Basic local alignment search tool. , 1990, Journal of molecular biology.

[5]  H. von Boehmer.  Shaping the T cell repertoire. , 2006, The Journal of Immunology.

[6]  John T. Chang,et al.  Asymmetric T Lymphocyte Division in the Initiation of Adaptive Immune Responses , 2007, Science.

[7]  D. Douek,et al.  TCR beta-chain sharing in human CD8+ T cell responses to cytomegalovirus and EBV. , 2008, Journal of immunology.

[8]  A. Casrouge,et al.  A direct estimate of the human alphabeta T cell receptor diversity. , 1999, Science.

[9]  Daniel C. Douek,et al.  The Role of Production Frequency in the Sharing of Simian Immunodeficiency Virus-Specific CD8+ TCRs between Macaques1 , 2008, The Journal of Immunology.

[10]  M. Weekes,et al.  The Memory Cytotoxic T-Lymphocyte (CTL) Response to Human Cytomegalovirus Infection Contains Individual Peptide-Specific CTL Clones That Have Undergone Extensive Expansion In Vivo , 1999, Journal of Virology.

[11]  D. Mason,et al.  A very high level of crossreactivity is an essential feature of the T-cell receptor. , 1998, Immunology today.

[12]  D. Price,et al.  The molecular basis for public T-cell responses? , 2008, Nature Reviews Immunology.

[13]  P. Kourilsky,et al.  Lineage relationships, homeostasis, and recall capacities of central– and effector–memory CD8 T cells in vivo , 2005, The Journal of experimental medicine.

[14]  A. Casrouge,et al.  Diversity of Human alpha beta T Cell Receptors , 2000, Science.

[15]  M. Mori,et al.  Loss of Naive T Cells and Repertoire Constriction Predict Poor Response to Vaccination in Old Primates , 2010, The Journal of Immunology.

[16]  Philippe Kourilsky,et al.  Vα and Vβ Public Repertoires Are Highly Conserved in Terminal Deoxynucleotidyl Transferase-Deficient Mice1 , 2005, The Journal of Immunology.

[17]  J. Cabaniols,et al.  Valpha and Vbeta public repertoires are highly conserved in terminal deoxynucleotidyl transferase-deficient mice. , 2005, Journal of immunology.

[18]  J. Altman,et al.  Individual variations in the murine T cell response to a specific peptide reflect variability in naive repertoires. , 1998, Immunity.

[19]  Marie-Paule Lefranc,et al.  IMGT, the international ImMunoGeneTics database. , 1997, Nucleic acids research.

[20]  J. Borghans,et al.  Diversity of Human αβ T Cell Receptors , 2000 .

[21]  Daniel C. Douek,et al.  Sharing of T cell receptors in antigen-specific responses is driven by convergent recombination , 2006, Proceedings of the National Academy of Sciences.

[22]  Daniel C. Douek,et al.  The Rational Design of an AIDS Vaccine , 2006, Cell.

[23]  Richard A Koup,et al.  T cell receptor recognition motifs govern immune escape patterns in acute SIV infection. , 2004, Immunity.

[24]  C. Hausl,et al.  Clonal selection of helper T cells is determined by an affinity threshold with no further skewing of TCR binding properties. , 2004, Immunity.

[25]  Dietmar Zehn,et al.  Complete but curtailed T cell response to very low affinity antigen , 2009, Nature.

[26]  A. McMichael,et al.  The T cell repertoire in infection and vaccination: implications for control of persistent viruses. , 2007, Current opinion in immunology.

[27]  D. Price,et al.  TCR β-Chain Sharing in Human CD8+ T Cell Responses to Cytomegalovirus and EBV1 , 2008, The Journal of Immunology.

[28]  P. Moss,et al.  Cytomegalovirus Seropositivity Drives the CD8 T Cell Repertoire Toward Greater Clonality in Healthy Elderly Individuals1 , 2002, The Journal of Immunology.

[29]  F. Celada,et al.  Narrowed TCR repertoire and viral escape as a consequence of heterologous immunity. , 2006, The Journal of clinical investigation.

[30]  S. Migueles,et al.  Avidity for antigen shapes clonal dominance in CD8+ T cell populations specific for persistent DNA viruses , 2005, The Journal of experimental medicine.

[31]  I. Messaoudi,et al.  The many important facets of T-cell repertoire diversity , 2004, Nature Reviews Immunology.

[32]  R. Ahmed,et al.  Continuous recruitment of naive T cells contributes to heterogeneity of antiviral CD8 T cells during persistent infection , 2006, The Journal of experimental medicine.

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

[34]  Janko Nikolich- Zcaron,et al.  Ageing and life-long maintenance of T-cell subsets in the face of latent persistent infections. , 2008 .

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

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

[37]  J. Nikolich-Žugich.  Ageing and life-long maintenance of T-cell subsets in the face of latent persistent infections , 2008, Nature Reviews Immunology.

[38]  G. Shellam,et al.  Memory inflation during chronic viral infection is maintained by continuous production of short-lived, functional T cells. , 2008, Immunity.

[39]  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.

[40]  M. Bonneville,et al.  Selection of T Cell Clones Expressing High-Affinity Public TCRs within Human Cytomegalovirus-Specific CD8 T Cell Responses1 , 2005, The Journal of Immunology.

[41]  James R. Knight,et al.  Genome sequencing in microfabricated high-density picolitre reactors , 2005, Nature.

[42]  P. Doherty,et al.  Structural determinants of T-cell receptor bias in immunity , 2006, Nature Reviews Immunology.

[43]  A. Cumano,et al.  The repertoires of circulating human CD8(+) central and effector memory T cell subsets are largely distinct. , 2003, Immunity.

[44]  Ramon Arens,et al.  Recruitment of Antigen-Specific CD8+ T Cells in Response to Infection Is Markedly Efficient , 2009, Science.

[45]  P. Moss,et al.  Comparative analysis of CD8+ T cell responses against human cytomegalovirus proteins pp65 and immediate early 1 shows similarities in precursor frequency, oligoclonality, and phenotype. , 2002, The Journal of infectious diseases.

[46]  S. Kalams,et al.  Limited T Cell Receptor Diversity of HCV-specific T Cell Responses Is Associated with CTL Escape , 2004, Journal of Experimental Medicine.

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