Charles A. Janeway

TAP1-dependent peptide translocation in vitro is ATP dependent and peptide selective

T cells detect infection of cells by recognizing peptide fragments of foreign proteins bound to class I molecules of the major histocompatibility complex (MHC) on the surface of the infected cell. MHC class I molecules bind peptide in the endoplasmic reticulum, and analysis of mutant cells has demonstrated that an adequate supply of peptides requires the presence of two genes in the MHC class II locus that encode proteins called transporters associated with antigen processing (TAP) 1 and 2. TAP1 and TAP2 are members of the ATP-binding cassette family of membrane translocators. In this study, we demonstrate in a cell-free system that TAP1 is part of an ATP-dependent, sequence-specific, peptide translocator.

An MHC interaction site maps to the amino-terminal half of the T cell receptor α chain variable domain

We have used cloned T cell receptor (TCR) genes from closely related CD4 T cell lines to probe the interaction of the TCR with several specific major histocompatibility complex (MHC) class II ligands. Complementarity determining region 3 (CDR3) equivalents of both alpha and beta TCR chains are required for antigen-MHC recognition. Our data provide novel information about the rotational orientation of TCR-MHC contacts in that exchange of the amino terminal portion of the TCR alpha chain containing the putative CDR1 and CDR2 regions results in both gain and loss of MHC class II specificity by the resulting receptor. These two TCRs differ primarily in recognition of polymorphisms in the second hypervariable region of the MHC class II alpha chain. These results document the involvement of CDR1 and/or CDR2 of the TCR alpha chain in MHC recognition and suggest a rotational orientation of this TCR to its MHC ligand.

Insulin-dependent diabetes mellitus and its animal models.

Major questions are still unanswered in the understanding of the pathogenesis of type 1 diabetes, including the important question of the nature of the autoantigen(s) recognised in the development of disease. In the nonobese diabetic mouse model, there is new evidence that insulin plays an important role: not only is it an antigen for pathogenic CD4+ T cells but also it is recognised by highly diabetogenic CD8+ T cells. Further studies using transgenic mice have also highlighted the role of glutamic acid decarboxylase as an autoantigen. It remains to be seen whether one or both of these autoantigens can be used in strategies to prevent human diabetes.

The Immunosuppressive Agent 15-Deoxyspergualin Functions by Inhibiting Cell Cycle Progression and Cytokine Production Following Naive T Cell Activation

Immunosuppressive agents are commonly used in the prevention of graft rejection following transplantation and in the treatment of autoimmunity. In this study, we examined the immunosuppressive mechanism of the drug 15-deoxyspergualin (DSG), which has shown efficacy in the enhancement of graft survival and in the treatment of autoimmunity. Using a murine model of chronic relapsing and remitting experimental autoimmune encephalomyelitis, we were able to demonstrate that DSG both delayed and reduced the severity of experimental autoimmune encephalomyelitis. Subsequent in vitro studies to examine the mechanism of immune suppression showed that DSG was not able to inhibit early activation of naive CD4 T cells, but DSG did effectively inhibit the growth of naive CD4 T cells after activation. An analysis of cell proliferation and cell cycle showed that DSG treatment led to a block in cell cycle progression 2–3 days following Ag stimulation. In addition, DSG treatment inhibited the production of IFN-γ by Th1 effector T cells. These studies suggest that CD4 T cells are a predominant target for DSG and the immunosuppressive effects of the drug may result from reduced CD4 T cell expansion and decreased polarization into IFN-γ-secreting Th1 effector T cells in the induction of certain autoimmune disorders.

The Structure and Function of T Cell Receptor Complexes

Lutilisation danticorps monoclonal anti-recepteur dans des etudes fonctionnelles a permis de montrer que la reticulation du recepteur est necessaire pour lactivation des cellules T helper. Le meme complexe moleculaire est implique dans la reconnaissance a la fois des complexes antigene: Ia-self et des molecules Ia non self. Lactivation du clone de cellules T implique les etapes suivantes: reticulation du recepteur, stimulation probable de liberation dIl-1; expression des recepteurs pour lIL-2 induite par IL-1, synthese dIL-2 stimulee par reticulation du recepteur, reception de lIl-2 endogene produite et multiplication cellulaire

SPECIFIC KILLER AND SPECIFIC AND NONSPECIFIC SUPPRESSOR ACTIVITIES INDUCED IN A PRIMARY MLC ARE MEDIATED BY DISTINCT T CELL SETS

ABSTRACT T cells derived from mixed leukocyte cultures (MLCs) make accelerated responses to the original stimulating antigen and little or no response to other alloantigens. The present experiments examine this finding to determine if it reflects positive selection of responding clones, suppression of nonresponding clones, or both. We found evidence for generation of at least four distinct types of T cells in a primary MLC: primed CTL precursors; cytotoxic T lymphocytes (CTLs); specific suppressor T cells; and non-specific suppressor T cells. Interestingly, primed CTL precursors were insensitive to suppressor T cells under the current experimental conditions, a finding which differentiated them from naive CTL precursors. An important outgrowth of this study was the discovery that the addition of pyrilamine, a histamine 1 receptor antagonist and local anesthetic, to a primary MLC permitted selective in vitro induction of specific suppressor T cells.

Self la-recognizing T cells undergo an ordered series of interactions with ia-bearing substrate cells of defined function during their development: A model

ConclusionA four-step scheme of cell interactions between self la-recognizing T cells in the helper T cell lineage and la-bearing substrate cells is proposed. The first interaction, with a veto cell, clears the repertoire of helper T cells specific for self Ia, or self antigens in association with self Ia. The second interaction, between helper T cells and Ia on thymic epithelium expands self Ia-recognizing T cells; T cell diotopes displayed on the epithelial cell surface may play the role of an internal antigenic image for this expansion. The third interaction occurs between antigen-presenting cell Ia plus nominal antigen and virgin Lyl T cells, leading to T cell activation and expansion. The fourth interaction involves B cells binding specific antigen via their Ig receptor and displaying self Ia, and this antigen-Ia complex is recognized by helper T cells, causing B cell proliferation and differentiation to antibody secretion. A regulatory pathway, involving suppressor T cells that recognize activated helper T cells via self Ia bound to the anti-self Ia receptor on the T cell surface, is also proposed. This model permits any or all of the proposed mechanisms of Ir gene ac tion, and is compatible with one or two site models of T cell receptors. Its main predictions are that Ia density is carefully regulated in substrate cells to allow both self tolerance and self recognition, in an ordered scheme of development.