A tale of two T cells.

I return last to the case that focused our attention in the first place on the mystery of how two TCRs that are so different can bind the same peptide/MHC class I ligand in a similar orientation (10xGarboczi, D.N, Ghosh, P, Utz, U, Fan, Q.R, Biddison, W.E, and Wiley, D.C. Nature. 1996; 384: 134–141Crossref | PubMed | Scopus (1065)See all References, 4xDing, Y-H, Smith, K.J, Garboczi, D.N, Utz, U, Biddison, W.E, and Wiley, D.C. Immunity. 1998; 8: 403–411Abstract | Full Text | Full Text PDF | PubMed | Scopus (363)See all References). In my opinion, positive intrathymic selection on the same peptide can, in normal mice, lead to what appears to be a highly diverse repertoire of TCRs, due to the initial rearrangement of the TCR β chain. This leads to T cells with similar recognition properties but diverse TCRs. This is seen also in single-peptide mice in which a diversity of TCRs recognize similar peptides. Presumably, the sequences of these TCRs will be highly distinct from one another, although how distinct they are is unclear at the present time. Suffice it to say that if two such different TCRs can recognize the same exact peptide/MHC complex, then attempts to modify T cell responses using strategies targeted at a particular TCR are unlikely to succeed. However, strategies that use antigen to manipulate the immune response look more favorable than they did initially, since the range of peptides that can be recognized appears to be limited, and within these limitations, perhaps the most important is the repertoire of self-peptides expressed within the thymus.These examples of “synonymous” TCRs dramatically affirm that it is the repertoire of self-peptides that selects the TCR that determine TCR specificity for a given antigenic peptide. This property, which has recently been described as degeneracy or cross-reactivity in the TCR repertoire (Mason 1998xMason, D. Immunol. Today, in press. 1998; See all ReferencesMason 1998), is a characteristic feature of TCRs. Immune responses, then, are derived from TCRs that are selected on a limited set of self-peptides but have different cross-reactivities with different foreign peptide/self-MHC complexes. The recent finding that mice expressing a limited set of self-peptides due to deletion of the H-2Ma gene cannot positively select several different TCR transgenes (13xGrubin, C.E, Kovats, S, DeRoos, P, and Rudensky, A.Y. Immunity. 1997; 7: 197–208Abstract | Full Text | Full Text PDF | PubMed | Scopus (162)See all References, 31xSurh, C.D, Lee, D.-S, Fung-Leung, W.-p, Karlsson, L, and Sprent, J. Immunity. 1997; 7: 209–219Abstract | Full Text | Full Text PDF | PubMed | Scopus (115)See all References) confirms that it is self-peptide bound to self-MHC molecules that is required to generate a normal TCR repertoire. In the case of the TCRs described by Wiley and colleagues (10xGarboczi, D.N, Ghosh, P, Utz, U, Fan, Q.R, Biddison, W.E, and Wiley, D.C. Nature. 1996; 384: 134–141Crossref | PubMed | Scopus (1065)See all References, 4xDing, Y-H, Smith, K.J, Garboczi, D.N, Utz, U, Biddison, W.E, and Wiley, D.C. Immunity. 1998; 8: 403–411Abstract | Full Text | Full Text PDF | PubMed | Scopus (363)See all References), this is carried to an extreme, in which only 1 of 17 TCR contacts is conserved, and the conserved amino acid makes a relatively unimportant contact at that. It will be interesting to examine other cases of TCRs that are unrelated but nevertheless recognize the same peptide/MHC ligand, as well as the 2C TCR that recognizes several highly distinct ligands with the same TCR. The molecular views of this interaction continue to fascinate and surprise us, and the surprises are likely to continue until we have assembled enough such structures to see general rules emerging (if they exist at all!).*To whom correspondence should be addressed (e-mail: charles.janeway@yale.edu).

[1]  Partho Ghosh,et al.  Structure of the complex between human T-cell receptor, viral peptide and HLA-A2 , 1996, Nature.

[2]  J. Shabanowitz,et al.  Specific recognition of thymic self-peptides induces the positive selection of cytotoxic T lymphocytes. , 1997, Immunity.

[3]  A. Berns,et al.  CD3 components at the surface of pro‐T cells can mediate pre‐T cell development in vivo , 1994, European journal of immunology.

[4]  J. Sprent,et al.  Thymic selection by a single MHC/peptide ligand produces a semidiverse repertoire of CD4+ T cells. , 1997, Immunity.

[5]  D. Schatz,et al.  Productive T-cell receptor beta-chain gene rearrangement: coincident regulation of cell cycle and clonality during development in vivo. , 1996, Genes & development.

[6]  C. Janeway,et al.  The imprint of intrathymic self-peptides on the mature T cell receptor repertoire. , 1997, Immunity.

[7]  C. Janeway,et al.  The specificity and orientation of a TCR to its peptide-MHC class II ligands. , 1996, Immunity.

[8]  M. Bevan,et al.  Specificity and flexibility in thymic selection , 1994, Nature.

[9]  M. Davis,et al.  Antigen-specific development of primary and memory T cells in vivo. , 1995, Science.

[10]  J. Zerrahn,et al.  The MHC Reactivity of the T Cell Repertoire Prior to Positive and Negative Selection , 1997, Cell.

[11]  J. Rothbard,et al.  Specific T cell recognition of minimally homologous peptides: evidence for multiple endogenous ligands. , 1995, Immunity.

[12]  A. Rudensky,et al.  Deficient positive selection of CD4 T cells in mice displaying altered repertoires of MHC class II-bound self-peptides. , 1997, Immunity.

[13]  M J Owen,et al.  T cell receptor beta chain gene rearrangement and selection during thymocyte development in adult mice. , 1994, Immunity.

[14]  H. Ruley,et al.  H2-M Mutant Mice Are Defective in the Peptide Loading of Class II Molecules, Antigen Presentation, and T Cell Repertoire Selection , 1996, Cell.

[15]  A. Hayday,et al.  Rearrangement and diversity of T cell receptor β chain genes in thymocytes: A critical role for the β chain in development , 1993, Cell.

[16]  L. Glimcher,et al.  Unopposed positive selection and autoreactivity in mice expressing class II MHC only on thymic cortex , 1996, Nature.

[17]  A. Tomlinson,et al.  Identification of a naturally occurring ligand for thymic positive selection. , 1997, Immunity.

[18]  Robyn L. Stanfield,et al.  An αβ T Cell Receptor Structure at 2.5 Å and Its Orientation in the TCR-MHC Complex , 1996, Science.

[19]  R. Atkins,et al.  Specific unresponsiveness of recirculating lymphocytes ater exposure to histocompatibility antigen in F 1 hybrid rats. , 1971, Nature: New biology.

[20]  L R Pease,et al.  Structural basis of plasticity in T cell receptor recognition of a self peptide-MHC antigen. , 1998, Science.

[21]  C. Benoist,et al.  Mice Lacking H2-M Complexes, Enigmatic Elements of the MHC Class II Peptide-Loading Pathway , 1996, Cell.

[22]  D. Wiley,et al.  Two human T cell receptors bind in a similar diagonal mode to the HLA-A2/Tax peptide complex using different TCR amino acids. , 1998, Immunity.

[23]  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.

[24]  S. Tonegawa,et al.  Mutations in T-cell antigen receptor genes α and β block thymocyte development at different stages , 1992, Nature.

[25]  P. A. Peterson,et al.  Antigen Presentation and T Cell Development in H2-M-Deficient Mice , 1996, Science.

[26]  P. Marrack,et al.  The Repertoire of T Cells Shaped by a Single MHC/Peptide Ligand , 1996, Cell.

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

[28]  T. Brocker.  Survival of Mature CD4 T Lymphocytes Is Dependent on Major Histocompatibility Complex Class II–expressing Dendritic Cells , 1997, The Journal of experimental medicine.

[29]  Ursula Esser,et al.  Mapping T-cell receptor–peptide contacts by variant peptide immunization of single-chain transgenics , 1992, Nature.

[30]  J. Strominger,et al.  Molecular mimicry in T cell-mediated autoimmunity: Viral peptides activate human T cell clones specific for myelin basic protein , 1995, Cell.