Abstract
Mice lacking the homeodomain transcription factor Nkx2-3 are either asplenic or develop a spleen of significantly reduced size with poorly organized white pulp. In this report, we analyze the effect of this mutation on B lymphocyte development and differentiation. Follicular dendritic cells in spleen, but not lymph node, of Nkx2-3(-/-) mice fail to express a developmental Ag (follicular dendritic cell-M2) and show an abnormal association with B cells, despite essentially normal expression of several chemokine genes. Bone marrow reconstitution studies show the splenic disorganization and absence of marginal zone B cells to be of stromal rather than hemopoietic origin. Furthermore, Nkx2-3(-/-) mice show an excess of conventional B cells in mesenteric lymph node and peritoneal cavity, whereas transitional B cells are rare in spleen but overrepresented in bone marrow. Finally, immunization of Nkx2-3(-/-) mice with a T cell-dependent Ag elicits clusters of germinal center B cells, although these fail to develop to the same extent as in controls and there is no evidence of affinity maturation in serum Ab. Similarly, Ab-forming cells fail to aggregate into foci early in the response. Collectively, these data indicate a substantial role for Nkx2-3 in the correct association of lymphocytes and splenic stromal elements that is independent of chemokine expression.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Anemia / blood
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Anemia / genetics
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Anemia / immunology
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Animals
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Antibody Formation / genetics*
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Antigens, T-Independent / administration & dosage
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Antigens, T-Independent / immunology
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B-Lymphocyte Subsets / immunology*
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B-Lymphocyte Subsets / metabolism
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B-Lymphocyte Subsets / pathology*
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Bone Marrow Transplantation / immunology
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Cell Differentiation / genetics
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Cell Differentiation / immunology
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Chemokines / biosynthesis
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Chemokines / genetics
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Dendritic Cells, Follicular / pathology
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Dextrans / administration & dosage
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Dextrans / immunology
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Dinitrobenzenes / administration & dosage
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Dinitrobenzenes / immunology
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Female
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Gene Expression Regulation / immunology
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Haptens
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Hemocyanins / administration & dosage
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Hemocyanins / immunology
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Homeodomain Proteins / genetics*
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Immunoglobulins / biosynthesis*
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Immunoglobulins / blood
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Leukocytosis / blood
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Leukocytosis / genetics
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Leukocytosis / immunology
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Spleen / abnormalities*
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Spleen / immunology*
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Spleen / metabolism
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Stromal Cells / immunology
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Stromal Cells / pathology
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T-Lymphocyte Subsets / immunology*
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T-Lymphocyte Subsets / metabolism
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T-Lymphocyte Subsets / pathology
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Zebrafish Proteins*
Substances
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4-hydroxy-3-nitrophenylacetyl-keyhole limpet hemocyanin
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Antigens, T-Independent
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Chemokines
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Dextrans
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Dinitrobenzenes
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Haptens
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Homeodomain Proteins
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Immunoglobulins
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Nkx2.3 protein, zebrafish
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Zebrafish Proteins
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Hemocyanins