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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 Responses¹

David Tarlinton^2,*, Amanda Light^*, Donald Metcalf^*, Richard P. Harvey^, and Lorraine Robb^*

^* Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Victor Chang Cardiac Research Institute, St. Vincent’s Hospital, Darlinghurst, New South Wales, Australia; and Faculties of Medicine and Life Sciences, University of New South Wales, Kensington, Australia

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.

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