The selective degradation of many short-lived proteins in eukaryotic cells is carried out by the ubiquitin system. In this pathway, proteins are targeted for degradation by covalent ligation to ubiquitin, a highly conserved small protein. Ubiquitin-mediated degradation of regulatory proteins plays important roles in the control of numerous processes, including cell-cycle progression, signal transduction, transcriptional regulation, receptor down-regulation, and endocytosis. The ubiquitin system has been implicated in the immune response, development, and programmed cell death. Abnormalities in ubiquitin-mediated processes have been shown to cause pathological conditions, including malignant transformation. In this review we discuss recent information on functions and mechanisms of the ubiquitin system. Since the selectivity of protein degradation is determined mainly at the stage of ligation to ubiquitin, special attention is focused on what we know, and would like to know, about the mode of action of ubiquitin-protein ligation systems and about signals in proteins recognized by these systems.

The Ubiquitin System

Dendritic cells (DCs) are antigen-presenting cells with a unique ability to induce primary immune responses. DCs capture and transfer information from the outside world to the cells of the adaptive immune system. DCs are not only critical for the induction of primary immune responses, but may also be important for the induction of immunological tolerance, as well as for the regulation of the type of T cell-mediated immune response. Although our understanding of DC biology is still in its infancy, we are now beginning to use DC-based immunotherapy protocols to elicit immunity against cancer and infectious diseases.

Immunobiology of Dendritic Cells

The adhesive interactions of cells with other cells and with the extracellular matrix are crucial to all developmental processes, but have a central role in the functions of the immune system throughout life Three families of cell-surface molecules regulate the migration of lymphocytes and the interactions of activated cells during immune responses

Adhesion receptors of the immune system.

For many years immunologists have been well served by the viewpoint that the immune system's primary goal is to discriminate between self and non-self. I believe that it is time to change viewpoints and, in this essay, I discuss the possibility that the immune system does not care about self and non-self, that its primary driving force is the need to detect and protect against danger, and that it does not do the job alone, but receives positive and negative communications from an extended network of other bodily tissues.

/pdf/tolerance-danger-and-the-extended-family-1qfdhdej1x.pdf

Tolerance, danger, and the extended family.

Fas ligand (FasL), a cell surface molecule belonging to the tumor necrosis factor family, binds to its receptor Fas, thus inducing apoptosis of Fas-bearing cells. Various cells express Fas, whereas FasL is expressed predominantly in activated T cells. In the immune system, Fas and FasL are involved in down-regulation of immune reactions as well as in T cell-mediated cytotoxicity. Malfunction of the Fas system causes lymphoproliferative disorders and accelerates autoimmune diseases, whereas its exacerbation may cause tissue destruction.

https://science.sciencemag.org/content/sci/267/5203/1449.full.pdf

The Fas Death Factor

The mechanism of self-tolerance is studied in T-cell-receptor transgenic mice expressing a receptor in many of their T cells for the male (H-Y) antigen in the context of class I H-2Db MHC antigens. Autospecific T cells are deleted in male mice. The deletion affects only transgene-expressing cells with a relatively high surface-density of CD8 molecules, including nonmature CD4+ CD8+ thymocytes, and is not caused by anti-idiotype cells.

/pdf/tolerance-in-t-cell-receptor-transgenic-mice-involves-21bpn9afqo.pdf

Tolerance in T-cell-receptor transgenic mice involves deletion of nonmature CD4 + 8 + thymocytes

T lymphocytes undergo selection events not only in the thymus, but also after they leave the thymus and reside in the periphery Peripheral selection was found to be dependent on T cell receptor (TCR)-ligand interactions but to differ from thymic selection with regard to specificity and mechanism Unlike thymic selection, peripheral selection required binding of antigen to the TCR, and it induced expansion of T cell clones Tolerance to self antigens that are restricted to the periphery occurred through the elimination of self-reactive T cells and by the clonal anergy, which was associated with down-regulation of the alpha beta TCR and CD8

https://science.sciencemag.org/content/sci/251/4998/1225.full.pdf

Peripheral Selection of the T Cell Repertoire

Thymus-derived lymphocytes (T cells) recognize antigen in the context of class I or class II molecules encoded by the major histocompatibility complex (MHC) by virtue of the heterodimeric alpha beta T-cell receptor (TCR). CD4 and CD8 molecules expressed on the surface of T cells bind to nonpolymorphic portions of class II and class I MHC molecules and assist the TCR in binding and possibly in signalling. The analysis of T-cell development in TCR transgenic mice has shown that the CD4/CD8 phenotype of T cells is determined by the interaction of the alpha beta TCR expressed on immature CD4+8+ thymocytes with polymorphic domains of thymic MHC molecules in the absence of nominal antigen. Here we provide direct evidence that positive selection of antigen-specific, class I MHC-restricted CD4-8+ T cells in the thymus requires the specific interaction of the alpha beta TCR with the restricting class I MHC molecule.

Positive selection of antigen-specific T cells in thymus by restricting MHC molecules

Article de synthese sur la selection du repertoire des cellules T parmi les cellules T immatures. L'etude est faite chez des souris transgeniques pour le recepteur des cellules T(TCR) ou une grande proportion des cellules T qui expriment un recepteur defini par sa specificite ainsi que par des anticorps monoclonaux peuvent etre suivies au cours de leur developpement dans differents environnements. La question des cellules T regulatrices putatives est abordee chez une souris qui a un systeme immunitaire quasi-monoclonal: des genes rearranges du TCR sont introduits dans des souris avec un deficit dans le rearrangement du TCR, les souris Scid, qui ont un immunodeficit mixte grave

Developmental biology of T cells in T cell-receptor transgenic mice.

Proteasomes degrade endogenous proteins. Two subunits, LMP-2 and LMP-7, are encoded in a region of the major histocompatibility complex (MHC) that is critical for class I-restricted antigen presentation. Mice with a targeted deletion of the gene encoding LMP-7 have reduced levels of MHC class I cell-surface expression and present the endogenous antigen HY inefficiently; addition of peptides to splenocytes deficient in LMP-7 restores wild-type class I expression levels. This demonstrates the involvement of LMP-7 in the MHC class I presentation pathway and suggests that LMP-7 functions as an integral part of the peptide supply machinery.

H von Boehmer

Papers

Tolerance in T-cell-receptor transgenic mice involves deletion of nonmature CD4 + 8 + thymocytes

Peripheral Selection of the T Cell Repertoire

Positive selection of antigen-specific T cells in thymus by restricting MHC molecules

Developmental biology of T cells in T cell-receptor transgenic mice.

MHC class I expression in mice lacking the proteasome subunit LMP-7