There are a number of mechanisms which cooperate to produce and maintain T-cell tolerance. First, and perhaps most important, is the clonal deletion in the thymus of T cells with high affinity for self antigens. However, to ensure that a wide repertoire of T cells is available in the periphery to combat foreign antigens, the threshold of clonal deletion may be set low enough so that T cells whose TCR's have sub-threshold affinity for self antigens mature and migrate to the periphery. T cells which recognize self antigen-derived peptides not expressed or presented in the thymus will also fail to be deleted. For those self-reactive T cells which are not deleted in the thymus, other mechanisms may produce tolerance, including an undefined alteration of signalling pathways which produces clonal anergy, and lowering the avidity of the TCR for its ligand by downregulating coreceptor and accessory molecules. Active suppression of T-cell responses in another well-described phenomenon whose mechanism is undefined. From our observations with the model systems discussed here, we have observed three distinct mechanisms by which T-cell tolerance can be circumvented, allowing autoimmune phenomena to occur. These mechanisms may have relevance for different types of autoimmune diseases seen in humans. In gld mice, the autoimmune disease seems to be related to a global defect in T-cell differentiation and function, which allows for the expansion of autoimmune B cells. While we showed that clonal deletion of V beta-bearing T cells is appropriate in certain cases, aberrant lymphokine secretion by the abnormal T cells or disruption of immune system regulation are most probably responsible for allowing autoantibody production. While human lupus erythematosis shares much of the pathology of lpr and gld mice, there is no expansion of T cells with a similar phenotype in human lupus. There are environmental factors which must play a role in the development of human lupus, since the incidence of the disease does not follow an absolute genetic pattern. The escape from clonal deletion and subsequent reactivation of autoimmune T cells which we observed in V beta 8.1 TCR-transgenic mice can be a model for human autoimmune diseases such as multiple sclerosis and type I diabetes, in which T cells are directed against a specific autoantigen. According to this model, susceptibility loci for autoimmune disease such as the MHC would function by producing different repertoires of T cells which in some cases could gain autoreactivity following activation.(ABSTRACT TRUNCATED AT 400 WORDS)

We have analyzed the origin and development of unusual CD4−CD8− α/β T cell receptor‐positive peripheral T cells produced in large numbers by mice homozygous for the gld mutation (C3H‐gld/gld). These mice may be an important model for investigating processes controlling T cell development. Bone marrow transfers demonstrated that the gld defect was intrinsic to bone marrow‐derived cells. Clonal deletion of potentially autoreactive cells was observed in peripheral gld CD4−CD8−, CD4+CD8−, and CD4−CD8+ T cells, as well as mature thymocytes. This suggests that gld CD4−CD8− T cells have passed through the thymus in ontogeny and that gld autoimmunity does not result from a general defect in elimination of self‐reactive thymocytes. These observations, combined with demethylation of the CD8 gene in the CD4−CD8− population, support prior expression of CD4 and/or CD8 in gld CD4−CD8− T cell ontogeny, perhaps at a CD4+CD8+ stage. Steroid sensitivity of gld thymocytes and CD4−CD8− T cells was normal. Therefore, we found no gross abnormalities in two major mechanisms of inducible cell death in the gld thymus, the clonal deletion process associated with tolerance and the steroid‐inducible endogenous endonuclease thought to be involved in apoptosis of unselected thymocytes. The data suggest that if gld CD4−CD8− T cells arise via escape from normal elimination in the thymus, they must do so by a novel defect in thymic selection (perhaps related to aberrant positive signals) and/or are expanded by an extrathymic process which allows clonal deletion to occur.

Thy-1 is a major cell surface molecule expressed on murine thymocytes and peripheral T cells. Its physiological function is unknown, but in vitro studies suggest that Thy-1 may transmit activation signals to T cells and may play a role in the growth and/or differentiation of thymocytes [Kroczek, R. A., Gunter, K. C., Seligmann, B. & Shevach, E. M. (1986) J. Immunol. 136, 4379-4384; Kroczek, R. A., Gunter, K. C., Germain, R. N. & Shevach, E. M. (1986) Nature (London) 322, 181-184]. However, not all mouse thymocytes are Thy-1+ [Scollay, R., Wilson, A., D'Amico, A., Kelly, K., Egerton, M., Pearse, M., Wu, L. & Shortman, K. (1988) Immunol. Rev. 104, 81-120]. In addition, C3H-gld/gld mice accumulate large numbers of Thy-1- (and Thy-1+) T-cell antigen receptor-positive CD8- CD4- (double negative) T cells in peripheral lymphoid organs. Our previous studies of these Thy-1- and Thy-1+ double negatives suggested that lack of Thy-1 expression correlated with diminished capacity to respond to T-cell stimuli. In this report, we describe a Thy-1- alpha/beta T-cell receptor-positive major histocompatibility complex-specific cytotoxic T-cell clone derived from C3H-gld/gld lymph node-residing cells. The data show that, at least in this system, Thy-1 (and CD8/CD4) expression is not required for growth, cytolytic activity, or expression of functional T-cell receptor complexes in vitro and raise the possibility that Thy-1 expression may not be obligatory in vivo for development of cytotoxic T-lymphocyte precursors in gld mice.

A monoclonal anti-idiotope termed 87.92.6 mimics the neutralization/cell-attachment site of the reovirus type 3 hemagglutinin (HA3). The second complementarity determining regions of the VH and VL of 87.92.6 share sequence similarity with a determinant on the HA3. We have used synthetic peptides (termed VH, VL, and Reo peptides, respectively) to probe the immunologic significance of this sequence similarity. Antibodies specific for Reo peptide or VL peptide neutralized reovirus type 3 infectivity. Although Reo peptide was an effective immunogen by itself, free VL peptide or VH peptide were unable to elicit antibodies unless they were linked to each other (VH-VL peptide). Immunization with reo peptide, 87.92.6, or the HA3 elicited a specific lymphocyte proliferative response to VH peptide, indicating that VH peptide may bear an important TH determinant. As found previously for 87.92.6, VL peptide elicited a delayed-type hypersensitivity response specific for reovirus type 3. Reovirus type 3 specific cytolytic lymphocytes specifically lysed targets coated with VH-VL peptide, but not VH or VL peptide alone. These results suggest that immune cross-reactivity between an external Ag and an internal image antibody can be understood at the primary structural level. These observations may have important implications for understanding the development of autoantibodies, network interactions, and the regulation of immune responses.

Immunological ReviewsVolume 104, Issue 1 p. 121-155 Molecular and Functional Properties of Novel T Cell Subsets in C3H-gld/gld and Nude Mice. Implications for Thymic and Extrathymic Maturation Katsuyuki Yui, Katsuyuki Yui Rm252, John Morgan Bldg., Division of Immunology, Department of Pathology and Laboratory Medicine, University of Pennsylvania, 36th & Hamilton Walk, Philadelphia. PA 19104-6082, U.S.A.Search for more papers by this authorScott Wadsworth, Scott Wadsworth Rm252, John Morgan Bldg., Division of Immunology, Department of Pathology and Laboratory Medicine, University of Pennsylvania, 36th & Hamilton Walk, Philadelphia. PA 19104-6082, U.S.A.Search for more papers by this authorAmy Yellen, Amy Yellen Rm252, John Morgan Bldg., Division of Immunology, Department of Pathology and Laboratory Medicine, University of Pennsylvania, 36th & Hamilton Walk, Philadelphia. PA 19104-6082, U.S.A.Search for more papers by this authorYasuhiro Hashimoto, Yasuhiro Hashimoto Rm252, John Morgan Bldg., Division of Immunology, Department of Pathology and Laboratory Medicine, University of Pennsylvania, 36th & Hamilton Walk, Philadelphia. PA 19104-6082, U.S.A.Search for more papers by this authorYasuo Kokai, Yasuo Kokai Rm252, John Morgan Bldg., Division of Immunology, Department of Pathology and Laboratory Medicine, University of Pennsylvania, 36th & Hamilton Walk, Philadelphia. PA 19104-6082, U.S.A.Search for more papers by this authorMark I. Greene, Mark I. Greene Rm252, John Morgan Bldg., Division of Immunology, Department of Pathology and Laboratory Medicine, University of Pennsylvania, 36th & Hamilton Walk, Philadelphia. PA 19104-6082, U.S.A.Search for more papers by this author Katsuyuki Yui, Katsuyuki Yui Rm252, John Morgan Bldg., Division of Immunology, Department of Pathology and Laboratory Medicine, University of Pennsylvania, 36th & Hamilton Walk, Philadelphia. PA 19104-6082, U.S.A.Search for more papers by this authorScott Wadsworth, Scott Wadsworth Rm252, John Morgan Bldg., Division of Immunology, Department of Pathology and Laboratory Medicine, University of Pennsylvania, 36th & Hamilton Walk, Philadelphia. PA 19104-6082, U.S.A.Search for more papers by this authorAmy Yellen, Amy Yellen Rm252, John Morgan Bldg., Division of Immunology, Department of Pathology and Laboratory Medicine, University of Pennsylvania, 36th & Hamilton Walk, Philadelphia. PA 19104-6082, U.S.A.Search for more papers by this authorYasuhiro Hashimoto, Yasuhiro Hashimoto Rm252, John Morgan Bldg., Division of Immunology, Department of Pathology and Laboratory Medicine, University of Pennsylvania, 36th & Hamilton Walk, Philadelphia. PA 19104-6082, U.S.A.Search for more papers by this authorYasuo Kokai, Yasuo Kokai Rm252, John Morgan Bldg., Division of Immunology, Department of Pathology and Laboratory Medicine, University of Pennsylvania, 36th & Hamilton Walk, Philadelphia. PA 19104-6082, U.S.A.Search for more papers by this authorMark I. Greene, Mark I. Greene Rm252, John Morgan Bldg., Division of Immunology, Department of Pathology and Laboratory Medicine, University of Pennsylvania, 36th & Hamilton Walk, Philadelphia. PA 19104-6082, U.S.A.Search for more papers by this author First published: August 1988 https://doi.org/10.1111/j.1600-065X.1988.tb00761.xCitations: 19AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Citing Literature Volume104, Issue1August 1988Pages 121-155 RelatedInformation

We report the first demonstration of Thy-1+, Lyt-2-, L3T4- MHC-specific CTL clones derived from the Lyt-2-, L3T4- subset of lymph node cells of C3H-gld/gld mice. These clones express alpha/beta heterodimeric TCRs on the cell surface and specifically recognize class I molecules on target cells. Lyt-2 and L3T4 molecules are therefore not essential for the induction, recognition, and killing of antigen-specific CTL. In addition, these studies suggest that antigen specificity development for class I structures may occur before Lyt-2 gene activation in the differentiation of T cells.