Altered positive selection due to corecognition of floppy peptide/MHC II conformers supports an integrative model of thymic selection

Thymocytes bearing the Eα52-68/I-Ab complex-specific 1H3.1 αβ T cell antigen receptor are positively selected in Ab-Ep [Ab-Ep transgenic, invariant chain (Ii)−/−, I-Aβb−/−] mice, where I-Ab molecules present only Eα52-68. Although Ii reintroduction led to deletion, I-Aβb reintroduction disrupted positive selection. T cell antigen receptor transgenic Ab-Ep I-Aβb+ mice had a large thymus with an increased absolute number of CD4+CD8+ cells and no overt signs of deletion. Unlike Ab-Ep Ii+ antigen-presenting cells, Ab-Ep I-Aβb+ antigen-presenting cells did not activate 1H3.1 T cells. However, their capacity to present Eα52-68 was intact. Thus, positive selection of 1H3.1 thymocytes on the tight compact Eα52-68/I-Ab complex is neutralized by the corecognition of loose compact self-peptide/I-Ab conformers that do not interfere with the cognate activation of mature 1H3.1 T cells. The data support the notion that the integration of distinct signals generated by the simultaneous recognition of multiple self-peptide/MHC complexes directs intrathymic selection of T cells.

[1]  A. Rudensky,et al.  Peptide loading in the endoplasmic reticulum accelerates trafficking of peptide:MHC class II complexes in B cells. , 1999, Journal of biomedical science.

[2]  C. Benoist,et al.  The influence of invariant chain on the positive selection of single T cell receptor specificities , 1995, European journal of immunology.

[3]  L. Spain,et al.  A peptide antigen antagonist prevents the differentiation of T cell receptor transgenic thymocytes. , 1994, Journal of immunology.

[4]  B. Fowlkes,et al.  Selective events in T cell development. , 1994, Annual review of immunology.

[5]  H. Boehmer.  Positive selection of lymphocytes , 1994, Cell.

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

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

[8]  E. Unanue,et al.  Cutting edge: negative selection of immature thymocytes by a few peptide-MHC complexes: differential sensitivity of immature and mature T cells. , 1999, Journal of immunology.

[9]  P. Marrack,et al.  Cell surface expression of class II MHC proteins bound by a single peptide. , 1995, Journal of immunology.

[10]  K. Ozato,et al.  Hybridoma cell lines secreting monoclonal antibodies to mouse H-2 and Ia antigens. , 1980, Journal of immunology.

[11]  M. Utsuyama,et al.  Positive and negative CD4+ thymocyte selection by a single MHC class II/peptide ligand affected by its expression level in the thymus. , 1997, Immunity.

[12]  A. Rudensky,et al.  Monoclonal antibody detection of a major self peptide. MHC class II complex. , 1992, Journal of immunology.

[13]  Mark M. Davis,et al.  A T Cell Receptor–specific Blockade of Positive Selection , 1999, The Journal of experimental medicine.

[14]  C. Nelson,et al.  Positive selection of transgenic receptor-bearing thymocytes by Kb antigen is altered by Kb mutations that involve peptide binding. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[15]  D. Kioussis,et al.  The agonist-antagonist balance in positive selection. , 1997, Immunology today.

[16]  G. J. V. Nossal,et al.  Negative selection of lymphocytes , 1994, Cell.

[17]  C. Janeway,et al.  A Role for Accessibility to Self-Peptide-Self-MHC Complexes in Intrathymic Negative Selection1 , 2001, The Journal of Immunology.

[18]  C. Janeway,et al.  Dual receptor T cells extend the immune repertoire for foreign antigens , 2002, Nature Immunology.

[19]  A. Rudensky,et al.  Requirement for diverse, low-abundance peptides in positive selection of T cells. , 1999, Science.

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

[21]  T. Nakayama,et al.  CD69 cell surface expression identifies developing thymocytes which audition for T cell antigen receptor-mediated positive selection. , 1993, International immunology.

[22]  A. Rudensky,et al.  Cathepsin L: critical role in Ii degradation and CD4 T cell selection in the thymus. , 1998, Science.

[23]  C. Janeway,et al.  Ligand thresholds at different stages of T cell development. , 1990, International immunology.

[24]  A. Rudensky,et al.  Sequence analysis of peptides bound to MHC class II molecules , 1991, Nature.

[25]  C. Janeway,et al.  On the Self-Referential Nature of Naive MHC Class II-Restricted T Cells1 , 2000, The Journal of Immunology.

[26]  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.

[27]  Kristin A. Hogquist,et al.  T cell receptor antagonist peptides induce positive selection , 1994, Cell.

[28]  E. Coligan.  Current protocols in immunology , 1991 .

[29]  C. Benoist,et al.  Mice lacking the MHC class II-associated invariant chain , 1993, Cell.

[30]  C. Janeway,et al.  Paradoxical intrathymic positive selection in mice with only a covalently presented agonist peptide , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[31]  C. Janeway,et al.  T-cell development, survival, and signalling: A new concept of the role of self-peptide: Self-MHC complexes , 1998 .

[32]  D. Kioussis,et al.  Interactions with multiple peptide ligands determine the fate of developing thymocytes. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[33]  C. Janeway,et al.  Functional and Phenotypic Evidence for Presentation of Eα52–68 Structurally Related Self-Peptide(s) in I-Eα-Deficient Mice1 , 2000, The Journal of Immunology.

[34]  S. Hedrick,et al.  In vivo and in vitro clonal deletion of double-positive thymocytes , 1992, The Journal of experimental medicine.

[35]  C. Benoist,et al.  Selection of a broad repertoire of CD4+ T cells in H-2Ma0/0 mice. , 1997, Immunity.

[36]  P. Möller,et al.  Non-co-ordinate expression of HLA-DR antigens and invariant chain. , 1988, Immunology.

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

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

[39]  W. Paul,et al.  Activation events during thymic selection , 1992, The Journal of experimental medicine.

[40]  P. Cresswell.  Invariant Chain Structure and MHC Class II Function , 1996, Cell.

[41]  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.

[42]  S. Tonegawa,et al.  Evidence for a differential avidity model of T cell selection in the thymus , 1994, Cell.

[43]  J. Sprent,et al.  Upregulation of surface markers on dying thymocytes , 1995, The Journal of experimental medicine.

[44]  C. Benoist,et al.  Positive Selection of T Cells Induced by Viral Delivery of Neopeptides to the Thymus , 1997, Science.

[45]  P. Ohashi,et al.  Positive and negative thymocyte selection induced by different concentrations of a single peptide. , 1994, Science.

[46]  M. Bevan,et al.  Positive selection of thymocytes. , 1995, Annual review of immunology.

[47]  P. Jensen,et al.  Positive Selection of Cd4+ T Cells Is Induced in Vivo by Agonist and Inhibited by Antagonist Peptides , 2001, The Journal of experimental medicine.

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

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

[50]  W. Swat,et al.  CD 69 expression during selection and maturation of CD4+8+ thymocytes , 1993, European journal of immunology.

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

[52]  D. Kioussis,et al.  Inhibition of thymocyte negative selection by T cell receptor antagonist peptides , 1996, European journal of immunology.

[53]  A. Rudensky.  Endogenous peptides associated with MHC class II and selection of CD4 T cells. , 1995, Seminars in Immunology.

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

[55]  C Benoist,et al.  Inhibition of thymocyte positive selection by natural MHC: peptide ligands , 1999, European journal of immunology.

[56]  P. Allen.  Peptides in positive and negative selection: A delicate balance , 1994, Cell.

[57]  A. Rudensky,et al.  Invariant Chain–independent Function of H-2M in the Formation of Endogenous Peptide–Major Histocompatibility Complex Class II Complexes In Vivo , 1998, The Journal of experimental medicine.

[58]  S. Jameson,et al.  Preselection Thymocytes Are More Sensitive to T Cell Receptor Stimulation Than Mature T Cells , 1998, The Journal of experimental medicine.

[59]  C. Janeway,et al.  T-cell development: A role for self-peptides in positive selection , 1999, Current Biology.

[60]  C. Goodnow,et al.  A critical role for complement in maintenance of self-tolerance. , 1998, Immunity.

[61]  A. Rudensky,et al.  Subtle conformational changes induced in major histocompatibility complex class II molecules by binding peptides. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[62]  I. Mellman,et al.  The invariant chain is required for intracellular transport and function of major histocompatibility complex class II molecules , 1994, The Journal of experimental medicine.

[63]  R. Germain,et al.  Defective major histocompatibility complex class II assembly, transport, peptide acquisition, and CD4+ T cell selection in mice lacking invariant chain expression , 1993, The Journal of experimental medicine.

[64]  C. Janeway,et al.  A novel MHC class II epitope expressed in thymic medulla but not cortex , 1989, Nature.

[65]  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.

[66]  C. Janeway,et al.  Designing and maintaining the mature TCR repertoire: the continuum of self-peptide:self-MHC complex recognition. , 1999, Immunity.

[67]  A. Rudensky,et al.  On the complexity of self , 1991, Nature.