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Blood, 1 March 2001, Vol. 97, No. 5, pp. 1336-1342
IMMUNOBIOLOGY
Dissociation of thymic positive and negative selection in
transgenic mice expressing major histocompatibility complex class I
molecules exclusively on thymic cortical epithelial cells
Myriam Capone,
Paola Romagnoli,
Friedrich Beermann,
H. Robson MacDonald, and
Joost P. M. van Meerwijk
From the Ludwig Institute for Cancer Research, Lausanne
Branch, University of Lausanne, Epalinges, Switzerland; the Institut
National de la Santé et de la Recherche Médicale (INSERM),
Toulouse, France; the Swiss Institute for Experimental Cancer Research,
Epalinges, Switzerland; and the Faculty of Life Sciences (UFR-SVT),
University Toulouse III, Toulouse, France.
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.
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