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Prepublished online as a Blood First Edition Paper on July 18, 2002; DOI 10.1182/blood-2002-06-1669.
Submitted June 6, 2002
Accepted July 4, 2002
Inefficient response of T lymphocytes to glycosylphosphatidylinositol-anchor-negative cells: implications for paroxysmal nocturnal hemoglobinuria
Yoshiko Murakami, Hiroshi Kosaka, Yusuke Maeda, Jun-ichi Nishimura, Norimitsu Inoue, Kazuhito Ohishi, Masaru Okabe, Junji Takeda, and Taroh Kinoshita*
Department of Immunoregulation, Osaka University Research Institute for Microbial Diseases, Suita, Osaka, Japan
Department of Dermatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
Department of Experimental Genome Research, Osaka University Genome Information Research Center, Suita, Osaka, Japan
Department of Environmental Research, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
* Corresponding author; email: tkinoshi{at}biken.osaka-u.ac.jp.
Paroxysmal nocturnal hemoglobinuria (PNH) is a hematopoietic stem cell disorder in which clonal cells defective in glycosylphosphatidylinositol (GPI) biosynthesis are expanded, leading to complement-mediated hemolysis. PNH is often associated with bone marrow suppressive conditions, such as aplastic anemia. One hypothetical mechanism for the clonal expansion of GPI-negative (GPI-) cells in PNH is that the mutant cells escape attack by autoreactive cytotoxic cells that are thought to be responsible for aplastic anemia. Here we studied two model systems. First, we made pairs of GPI+ and GPI- EL4 cells that expressed MHC class II molecules and various types of ovalbumin. When the GPI-anchored form of ovalbumin was expressed on GPI+ and GPI- cells, only the GPI+ cells presented ovalbumin to ovalbumin-specific CD4+ T cells, indicating that if a putative autoantigen recognized by cytotoxic cells is a GPI-anchored protein, GPI- cells are less sensitive to cytotoxic cells. Second, antigen-specific as well as alloreactive CD4+ T cells responded less efficiently to GPI- than GPI+ cells in proliferation assays. In vivo, when GPI- and GPI+ fetal liver cells, and CD4+ T cells alloreactive to them were cotransplanted into irradiated hosts, the contribution of GPI- cells in peripheral blood cells was significantly higher than that of GPI+ cells. The results obtained with the second model suggest that certain GPI-anchored protein on target cells is important for recognition by T cells. These results provide the first experimental evidence for the hypothesis that GPI- cells escape from immunological attack.
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