A molecular chart of thymocyte positive selection

As a new slant on T lymphocyte repertoire selection, we have examined batteries of TCR sequences in thymi from transgenic mice engineered to exhibit limited, focussed TCR diversity. We have tracked the fate of differentiating thymocytes expressing a set of particular TCR through the positive selection process. Subtly different TCR sequences can promote different maturation pathways and commitment choices. Two distinct routes are followed by CD8‐lineage cells interacting with MHC class I molecules, via TCRhi CD4+CD8+ or CD4+CD8int intermediates, while CD4‐lineage cells mature exclusively via a CD4+CD8int stage. The CD8‐lineage routes are partially exclusive, indicating that the latter cell type is not always preceded by the former. The distribution of sequences also indicates that CD4 / CD8‐lineage commitment is not strictly correlated with the class of MHC molecule engaged, and that some mechanism prevents mismatched intermediates from achieving full maturity.

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

[2]  S. Rastan,et al.  Lymphoid development in mice congenitally lacking T cell receptor alpha beta-expressing cells. , 1992, Science.

[3]  R. Germain,et al.  Unexpectedly complex regulation of CD4/CD8 coreceptor expression supports a revised model for CD4+CD8+ thymocyte differentiation. , 1996, Immunity.

[4]  B. Rocha,et al.  Generation of mature T cell populations in the thymus: CD4 or CD8 down‐regulation occurs at different stages of thymocyte differentiation , 1994, European journal of immunology.

[5]  A. Singer,et al.  Asymmetric signaling requirements for thymocyte commitment to the CD4+ versus CD8+ T cell lineages: a new perspective on thymic commitment and selection. , 1995, Immunity.

[6]  A. Singer,et al.  Coreceptor reversal in the thymus: signaled CD4+8+ thymocytes initially terminate CD8 transcription even when differentiating into CD8+ T cells. , 2000, Immunity.

[7]  W. Heath,et al.  Intermediate steps in positive selection: differentiation of CD4+8int TCRint thymocytes into CD4-8+TCRhi thymocytes , 1995, The Journal of experimental medicine.

[8]  R. Germain,et al.  The duration of antigen receptor signalling determines CD4+ versus CD8+ T-cell lineage fate , 2000, Nature.

[9]  P. Fink,et al.  Identification of conserved T cell receptor CDR3 residues contacting known exposed peptide side chains from a major histocompatibility complex class I‐bound determinant , 1993, European journal of immunology.

[10]  A. Singer,et al.  Signals involved in CD4/CD8 lineage commitment: current concepts and potential mechanisms. , 1999, Seminars in immunology.

[11]  M. Bevan,et al.  CD8 lineage commitment in the absence of CD8. , 1997, Immunity.

[12]  C. Benoist,et al.  Visualization of CD4/CD8 T Cell Commitment , 1998, The Journal of experimental medicine.

[13]  D. Littman,et al.  Evidence for a stochastic mechanism in the differentiation of mature subsets of T lymphocytes , 1993, Cell.

[14]  C. Benoist,et al.  A Challenge to the Instructive Model of Positive Selection , 1993, Immunological reviews.

[15]  D. Gray,et al.  Mice lacking MHC class II molecules , 1991, Cell.

[16]  C. Benoist,et al.  Amino Acids Specifying MHC Class Preference in TCR Vα2 Regions , 1999, The Journal of Immunology.

[17]  V. Kouskoff,et al.  Cassette vectors directing expression of T cell receptor genes in transgenic mice. , 1995, Journal of immunological methods.

[18]  N. Killeen,et al.  MHC class II-specific T cells can develop in the CD8 lineage when CD4 is absent. , 1996, Immunity.

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

[20]  U. Bommhardt,et al.  CD3 Ligation on Immature Thymocytes Generates Antagonist-like Signals Appropriate for CD8 Lineage Commitment, Independently of  T Cell Receptor Specificity , 1998, The Journal of experimental medicine.

[21]  P. Fink,et al.  Positive selection of thymocytes. , 1995, Annual review of immunology.

[22]  W. Fanslow,et al.  Constitutive CD8 expression allows inefficient maturation of CD4+ helper T cells in class II major histocompatibility complex mutant mice , 1994, The Journal of experimental medicine.

[23]  C. Benoist,et al.  CD4/CD8 lineage commitment: matching fate with competence , 1998, Immunological reviews.

[24]  C. Benoist,et al.  Role of coreceptors in positive selection and lineage commitment. , 1994, The EMBO journal.

[25]  D. Littman,et al.  The regulation of CD4 and CD8 coreceptor gene expression during T cell development. , 1999, Annual review of immunology.

[26]  C. Janeway,et al.  A molecular map of T cell development. , 1998, Immunity.

[27]  H. von Boehmer.  Developmental biology of T cells in T cell-receptor transgenic mice. , 1990, Annual review of immunology.

[28]  C Benoist,et al.  Positive selection of thymocytes induced by gene transfer: MHC class II-mediated selection of CD8 lineage cells. , 1999, International immunology.

[29]  J. Alberola-Ila,et al.  Lck activity controls CD4/CD8 T cell lineage commitment. , 2000, Immunity.

[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]  H. Pircher,et al.  Evidence for a selective and multi‐step model of T cell differentiation: CD4+CD8low thymocytes selected by a transgenic T cell receptor on major histocompatibility complex class I molecules , 1994, European journal of immunology.