Inefficient response of T lymphocytes to glycosylphosphatidylinositol anchor–negative cells: implications for paroxysmal nocturnal hemoglobinuria

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Abstract
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−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 2 model systems. First, we made pairs of GPI+ and GPI− EL4 cells that expressed major histocompatibility complex (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 immunologic attack.