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Prepublished online as a Blood First Edition Paper on December 27, 2002; DOI 10.1182/blood-2002-06-1855.
Submitted June 24, 2002
Accepted December 16, 2002
Promoter IV of the class II transactivator gene is essential for positive selection of CD4+ T cells
Jean-Marc Waldburger, Simona Rossi, Georg A Hollander, Hans-Reimer Rodewald, Walter Reith, and Hans Acha-Orbea*
Lausanne Branch, Ludwig Institute for Cancer Research, Epalinges, Switzerland
Institute of Biochemistry, University of Lausanne, Epalinges, Switzerland
Department of Genetics and Microbiology, University of Geneva Medical School, Geneva, Switzerland
Department of Immunology, University Clinics Ulm, Ulm, Germany
Departments of Research and Clinical-biological Sciences, Division of Pediatric Immunology, The Children's Hospital, University of Basel, Basel, Switzerland
* Corresponding author; email: Hans.Acha-Orbea{at}ib.unil.ch.
MHC class II (MHCII) expression is regulated by the transcriptional coactivator CIITA. Positive selection of CD4+ T cells is abrogated in mice lacking one of the promoters (pIV) of the Mhc2ta gene. This is entirely due to the absence of MHCII expression in thymic epithelia, as demonstrated by bone marrow transfer experiments between wild-type and pIV-/- mice. Medullary thymic epithelial cells (mTEC) are also MHCII negative in pIV-/- mice. Bone marrow derived, professional antigen presenting cells (APC) retain normal MHCII expression in pIV-/- mice, including those believed to mediate negative selection in the thymic medulla. Endogenous retroviruses thus retain their ability to sustain negative selection of the residual CD4+ thymocytes in pIV-/- mice. Interestingly, the passive acquisition of MHCII molecules by thymocytes is abrogated in pIV-/- mice. This identifies thymic epithelial cells as the source of this passive transfer. In peripheral lymphoid organs, the CD4+ T cell population of pIV-/- mice is quantitatively and qualitatively comparable to that of MHCII deficient mice. It comprises a high proportion of CD1 restricted NKT cells, which results in a bias of the V repertoire of the residual CD4+ T cell population. We have also addressed the identity of the signal that sustains pIV expression in cortical epithelia. We found that the Jak/STAT pathways activated by the common  chain (CD132) or common chain (CDw131) cytokine receptors are not required for MHCII expression in thymic cortical epithelia.
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