Selecting Ligand-Chains Is Highly Dependent β-and α Transgenic TCR Transgenic Mice in Which Usage of

We have produced a TCR transgenic mouse that uses a TCR derived from a Th1 clone that is specific for residues 64 to 76 of the d allele of murine hemoglobin presented by I-E k. Examination of these TCR transgenic mice on an H-2 k/k background that expressed the nonstimulatory s allele of murine hemoglobin revealed that these mice express many endogenous TCR chains from both ␣ and ␤ loci. We found that this transgenic TCR is also very inefficient at mediating ␤ selection, thereby showing a direct linkage between ␤ selection and allelic exclusion of TCR ␤. We have also examined these mice on MHC backgrounds that have reduced levels of I-E k and found that positive selection of cells with high levels of the transgenic TCR depends greatly on the ligand density. Decreasing the selecting ligand density is a means of reducing the number of available selecting niches, and the data reveal that the 3.L2 TCR is used sparingly for positive selection under conditions where the number of niches becomes limiting. The results, therefore, show a way that T cells may get to the periphery with two self-restricted TCRs: one that efficiently mediates positive selection, and another that is inefficient at positive selection with the available niches. A key event in thymic development of T cells in the ␣␤ lineage is the successful rearrangement of a TCR ␤-chain gene (1– 4). This first major checkpoint in the thymic developmental process has been called ␤ selection (5, 6). The initial ␤ rearrangement takes place in CD4 Ϫ CD8 Ϫ thymo-cytes, and successful rearrangements produce functional TCR ␤-chains that pair with the pre-T␣-chain (7). The expression of the ␤/pre-T␣ complex on the cell surface leads to three main consequences: 1) proliferation of these thymocytes, 2) up-regulation of the CD4 and CD8 coreceptors, and 3) an end to rearrangement at the ␤ locus (2). The result is an expanded CD4 ϩ CD8 ϩ population of thymocytes that all have at least one ␤-chain that is competent for cell surface expression. Rearrangement is stopped quickly at the ␤ locus once one functional ␤-chain has been produced, and it is observed that almost all T cells have only a single functionally rearranged ␤ (8). This mechanism is therefore termed allelic exclusion , but does not exclude the possibility that both ␤ loci can functionally rearrange. Indeed, studies on both human and mouse lymphocytes …

[1]  T. Manser,et al.  A Novel Mechanism for B Cell Repertoire Maturation Based on Response by B Cell Precursors to Pre–B Receptor Assembly , 1998, The Journal of experimental medicine.

[2]  J. Buer,et al.  Essential role of the pre-T cell receptor in allelic exclusion of the T cell receptor beta locus. , 1997, Immunity.

[3]  M. Davis,et al.  A range of CD4 T cell tolerance: partial inactivation to organ-specific antigen allows nondestructive thyroiditis or insulitis. , 1997, Immunity.

[4]  D. Yelon,et al.  Structurally similar TCRs differ in their efficiency of positive selection. , 1997, Journal of immunology.

[5]  P. Allen,et al.  Structural basis for T cell recognition of altered peptide ligands: a single T cell receptor can productively recognize a large continuum of related ligands , 1996, The Journal of experimental medicine.

[6]  B. Stockinger,et al.  Expression of a second receptor rescues self-specific T cells from thymic deletion and allows activation of autoreactive effector function. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[7]  N. Gascoigne,et al.  Allelic exclusion of mouse T cell receptor α chains occurs at the time of thymocyte TCR up-regulation , 1995 .

[8]  A. Lanzavecchia,et al.  Serial triggering of many T-cell receptors by a few peptide–MHC complexes , 1995, Nature.

[9]  A. Lanzavecchia,et al.  Normal T lymphocytes can express two different T cell receptor beta chains: implications for the mechanism of allelic exclusion , 1995, The Journal of experimental medicine.

[10]  M. Bonneville,et al.  Dual T cell receptor beta chain expression on human T lymphocytes , 1995, The Journal of experimental medicine.

[11]  C. Janeway,et al.  T cells with two functional antigen-specific receptors. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[12]  M. Bonneville,et al.  Dual T Cell Receptor B Chain Expression on Human T Lymphocytes By Francois Davodeau,* Marie-Alix Peyrat,* Francois Romagn6,~ , 1995 .

[13]  C. Benoist,et al.  Evidence for a single-niche model of positive selection. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[14]  P. Allen,et al.  Th2 cell clonal anergy as a consequence of partial activation , 1994, The Journal of experimental medicine.

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

[16]  M P Cooke,et al.  Resting and anergic B cells are defective in CD28-dependent costimulation of naive CD4+ T cells , 1994, The Journal of experimental medicine.

[17]  A. Zlotnik,et al.  Control points in early T-cell development. , 1993, Immunology today.

[18]  A. Hayday,et al.  A novel disulfide-linked heterodimer on pre—T cells consists of the T cell receptor β chain and a 33 kd glycoprotein , 1993, Cell.

[19]  A. Lanzavecchia,et al.  Expression of two T cell receptor alpha chains: dual receptor T cells. , 1993, Science.

[20]  R. Perlmutter,et al.  Protein tyrosine kinase p56lck controls allelic exclusion of T-cell receptor β-chain genes , 1993, Nature.

[21]  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.

[22]  F. Alt,et al.  Restoration of T cell development in RAG-2-deficient mice by functional TCR transgenes. , 1993, Science.

[23]  A. Hayday,et al.  Is TCR beta expression an essential event in early thymocyte development? , 1993, Immunology today.

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

[25]  Y. Uematsu,et al.  Exclusion and inclusion of α and β T cell receptor alleles , 1992, Cell.

[26]  Susumu Tonegawa,et al.  RAG-1-deficient mice have no mature B and T lymphocytes , 1992, Cell.

[27]  S. Buus,et al.  Complete dissection of the Hb(64-76) determinant using T helper 1, T helper 2 clones, and T cell hybridomas. , 1992, Journal of immunology.

[28]  J. Casanova,et al.  T cell receptor genes in a series of class I major histocompatibility complex-restricted cytotoxic T lymphocyte clones specific for a Plasmodium berghei nonapeptide: implications for T cell allelic exclusion and antigen-specific repertoire , 1991, The Journal of experimental medicine.

[29]  H. Boehmer,et al.  Kinetics and efficacy of positive selection in the thymus of normal and T cell receptor transgenic mice , 1991, Cell.

[30]  M. Egerton,et al.  The kinetics of T cell antigen receptor expression by subgroups of CD4+8+ thymocytes: delineation of CD4+8+3(2+) thymocytes as post- selection intermediates leading to mature T cells , 1991, The Journal of experimental medicine.

[31]  Mark M. Davis,et al.  The effects of MHC gene dosage and allelic variation on T cell receptor selection , 1990, Cell.

[32]  S. Ryser,et al.  In transgenic mice the introduced functional T cell receptor β gene prevents expression of endogenous β genes , 1988, Cell.

[33]  C. Janeway,et al.  The biologic activity of anti-T cell receptor V region monoclonal antibodies is determined by the epitope recognized. , 1988, Journal of immunology.

[34]  S. Ryser,et al.  In transgenic mice the introduced functional T cell receptor beta gene prevents expression of endogenous beta genes. , 1988, Cell.

[35]  V. E. Williams,et al.  The murine E alpha immune response gene. , 1983, Cell.

[36]  K. Rajewsky,et al.  A new mouse myeloma cell line that has lost immunoglobulin expression but permits the construction of antibody-secreting hybrid cell lines. , 1979, Journal of immunology.