Dissociation of thymic positive and negative selection in transgenic mice expressing major histocompatibility complex class I molecules exclusively on thymic cortical epithelial cells.
Thymic positive and negative selection of developing T lymphocytes confronts us with a paradox: How can a T-cell antigen receptor (TCR)-major histocompatibility complex (MHC)/peptide interaction in the former process lead to transduction of signals allowing for cell survival and in the latter induce programmed cell death or a hyporesponsive state known as anergy? One of the hypotheses put forward states that the outcome of a TCR-MHC/peptide interaction depends on the cell type presenting the selecting ligand to the developing thymocyte. Here we describe the development and lack of self-tolerance of CD8(+) T lymphocytes in transgenic mice expressing MHC class I molecules in the thymus exclusively on cortical epithelial cells. Despite the absence of MHC class I expression on professional antigen-presenting cells, normal numbers of CD8(+) cells were observed in the periphery. Upon specific activation, transgenic CD8(+) T cells efficiently lysed syngeneic MHC class I(+) targets in vitro and in vivo, indicating that thymic cortical epithelium (in contrast to medullary epithelium and antigen-presenting cells of hematopoietic origin) is incapable of tolerance induction. Thus, compartmentalization of the antigen-presenting cells involved in thymic positive selection and tolerance induction can (at least in part) explain the positive/negative selection paradox.
Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, Epalinges, Switzerland.
M
M
Capone
P
P
Romagnoli
F
F
Beermann
H R
HR
MacDonald
J P
JP
van Meerwijk
D000818:Animals; D001324:Autoantigens / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D003601:Cytotoxicity Tests, Immunologic; D004847:Epithelial Cells / Q000276:immunology* / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D053547:Keratin-14; D007633:Keratins / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic / Q000276:immunology; D011401:Promoter Regions, Genetic; D012641:Selection, Genetic; D013950:Thymus Gland / Q000166:cytology*; D001613:beta 2-Microglobulin / Q000235:genetics
D001324:Autoantigens; D015395:Histocompatibility Antigens Class I; C507540:KRT14 protein, human; D053547:Keratin-14; C507446:Krt14 protein, mouse; D001613:beta 2-Microglobulin; D007633:Keratins