Architectural defects in the spleens of Nkx2-3-deficient mice are intrinsic and associated with defects in both B cell maturation and T cell-dependent immune responses.
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.
Tarlinton
David
D
Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
Light
Amanda
A
Metcalf
Donald
D
Harvey
Richard P
RP
Robb
Lorraine
L
D000740:Anemia / Q000097:blood / Q000235:genetics / Q000276:immunology; D000818:Animals; D000917:Antibody Formation / Q000235:genetics*; D000955:Antigens, T-Independent / Q000008:administration & dosage / Q000276:immunology; D016175:B-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D016026:Bone Marrow Transplantation / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D018925:Chemokines / Q000096:biosynthesis / Q000235:genetics; D020566:Dendritic Cells, Follicular / Q000473:pathology; D003911:Dextrans / Q000008:administration & dosage / Q000276:immunology; D004136:Dinitrobenzenes / Q000008:administration & dosage / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D006241:Haptens; D006433:Hemocyanins / Q000008:administration & dosage / Q000276:immunology; D018398:Homeodomain Proteins / Q000235:genetics*; D007136:Immunoglobulins / Q000096:biosynthesis* / Q000097:blood; D007964:Leukocytosis / Q000097:blood / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013154:Spleen / Q000002:abnormalities* / Q000276:immunology* / Q000378:metabolism; D017154:Stromal Cells / Q000276:immunology / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D029961:Zebrafish Proteins
C098951:4-hydroxy-3-nitrophenylacetyl-keyhole limpet hemocyanin; D000955:Antigens, T-Independent; D018925:Chemokines; D003911:Dextrans; D004136:Dinitrobenzenes; D006241:Haptens; D018398:Homeodomain Proteins; D007136:Immunoglobulins; C102935:Nkx2.3 protein, zebrafish; D029961:Zebrafish Proteins; D006433:Hemocyanins