Katsuyuki Yui

Molecular and functional properties of novel T cell subsets in C3H-gld/gld and nude mice. Implications for thymic and extrathymic maturation.

This review is primarily concerned with unusual subsets of thymus-derived lymphocytes which our laboratory has analyzed. One of the many difficulties encountered in the study of T-cell differentiation pathways is that the actual numbers of T-lineage cells at a given stage of development is limited. Several methods have been conceived to overcome these difilculties, including establishment of precursor T-cell clones, thymocyte tumors or hybridomas, and microculture systems. Our laboratory has taken advantage of the gid mutation, which has dramatic effects on lymphocyte accumulation and positioning patterns. We will briefly discuss T-cell differentiation in general and then describe our experiments concerning novel T-cell subsets in peripheral lymph nodes of C3Hgld/gld mice. Finally, we will discuss our views concerning the origins of these novel T-ceil subsets and their relation to normal thymic differentiation.

Gld and Lpr Mice: Single Gene Mutant Models for Failed Self Tolerance

Mice homozygous for the gld or lpr mutations develop autoimmunity, and a lymphoproliferative disorder involving accumulation of huge numbers of unusual CD4-CD8-TCR alpha beta lo T cells. Here we review our past work with gld mice, and attempt to explain lymphoproliferation in terms of current models of T cell maturation and self-tolerance induction. The availability of molecular probes to the gene products of lpr and gld should shortly lead to a better understanding of the acquisition of self tolerance during T cell maturation and of autoimmunity.

Modulation of T cell responses with MHC-derived peptides

SummaryT cells are activated by an interaction of their TCRs with a complex made up of antigenic peptide bound to the interhelical groove of MHC molecules. The helices lining the antigen binding groove of MHC molecules are felt to contribute several contact residues for TCR binding. Peptides derived from the amino acid sequences of these helices may be capable of modulating immune responses and aiding in the dissection of immune recognition. These studies address the effects of a peptide derived from the sequence of amino acids 68–83 of the IAkβ1 domain (IAk 68–83) predicted to represent a portion of an antigen-binding helix on the IAk molecule. The IAk 68–83 peptide is bound a monoclonal anti-IAk antibody and inhibits its binding to IAk-bearing cells. The IAk 68–83 peptide inhibits antigen-dependent activation of the IAk+con-albumin restricted T cell clone D10.G4, and this effect is more pronounced at lower doses of antigen-presenting cells. The free peptide has a small effect in limiting binding of anticlonotypic antibodies to D10.G4, and a multivalent form bound to BSA has a more pronounced effect in this regard. The BSA-peptide conjugate, when fluoresceinated, specifically stained D10.G4 cells, and this was specifically competed by unfluoresceinated IAk 68–83 peptide-BSA conjugate, as well as by anticlonotype. These results suggest that peptides derived from the predicted helical region of MHC class II molecules may have a direct interaction with T cell receptors. Such peptides may be capable of modulating immune responses in a physiologically significant manner.

T-Cell receptor and autoimmune disease

SummarySince the genes encoding the TCR have been cloned, their structure, organization, pattern of rearrangement, diversification and expression in ontogeny have been classified. However, there are still many important questions to be addressed, such as the nature of thymic education, tolerance, the mechanism of MHC-restricted antigen recognition and the relation between TCR repertoire and autoimmunity. In the future, new approaches to study these issues, such as transgenic mice, X-ray crystallography, and severe combined immune deficiency mice reconstituted with human hematopoietic cells will lead to a more profound understanding of these questions. This will hopefully allow us to manipulate the immune response in different and more effective ways than are currently available.