Glycosylphosphatidylinositol-linked proteins are required for maintenance of a normal peripheral lymphoid compartment but not for lymphocyte development.
Surface proteins tethered to the membrane through a glycosylphosphatidylinositol (GPI) anchor are deficient in the blood cells of patients with paroxysmal nocturnal hemoglobinuria (PNH) as result of a somatic mutation, in a hematopoietic stem cell, of the X-linked phosphatidylinositolglycan complementation group A (PIG-A) gene. In PNH patients, compared to the large numbers of GPI-deficient myeloid cells, the proportion of GPI-deficient lymphocytes tends to be low, and therefore the impact of GPI deficiency on immune function has been unclear. We have obtained complementation by Pig-a(-) embryonic stem (ES) cells of Rag(-/-) blastocysts, and we show that Pig-a(-) ES cells are able to reconstitute the T cell and B cell compartments of Rag(-/-) mice. Although these mice were immunologically competent, by comparison with appropriate controls we detected several abnormalities: (1) increased levels of IgG; (2) high frequency/titers of anti-nuclear antibodies; (3) markedly reduced delayed hypersensitivity; and (4) impaired activation-induced lymphocyte death in vitro. In some cases, aging Pig-a(-)/Rag(-/-) chimeric mice developed lymphadenopathy and polyclonal T cell and B cell expansion. Thus, GPI-linked proteins are not required for lymphocyte development but they are required for normal lymphocyte function and for maintaining normal peripheral lymphoid homeostasis.
Department of Human Genetics, Memorial Sloan-Kettering Cancer Center, New York, USA.
Monica
M
Bessler
Vittorio
V
Rosti
Yufeng
Y
Peng
Giorgio
G
Cattoretti
Rosario
R
Notaro
Satomi
S
Ohsako
Keith B
KB
Elkon
Lucio
L
Luzzatto
D000375:Aging / Q000276:immunology; D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D015551:Autoimmunity / Q000235:genetics / Q000502:physiology; D001755:Blastocyst; D002454:Cell Differentiation; D019070:Cell Lineage; D002678:Chimera / Q000276:immunology; D004624:Embryo Transfer; D005260:Female; D018390:Gene Targeting; D005816:Genetic Complementation Test; D017261:Glycosylphosphatidylinositols / Q000502:physiology*; D006410:Hematopoiesis / Q000235:genetics / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000473:pathology; D006457:Hemoglobinuria, Paroxysmal / Q000235:genetics / Q000276:immunology; D018398:Homeodomain Proteins / Q000502:physiology; D006706:Homeostasis; D006801:Humans; D006942:Hypergammaglobulinemia / Q000235:genetics; D006968:Hypersensitivity, Delayed / Q000235:genetics; D007153:Immunologic Deficiency Syndromes / Q000235:genetics*; D008214:Lymphocytes / Q000166:cytology*; D008232:Lymphoproliferative Disorders / Q000235:genetics; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D013047:Specific Pathogen-Free Organisms; D013234:Stem Cells / Q000378:metabolism
D000974:Antibodies, Antinuclear; D017261:Glycosylphosphatidylinositols; D018398:Homeodomain Proteins; D008565:Membrane Proteins; C080086:phosphatidylinositol glycan-class A protein; C064658:RAG-1 protein