Distinct changes in adult lymphopoiesis in Rag2 −/− mice fully reconstituted by α4-deficient adult bone marrow cells

Abstract

alpha4 Integrins are major players in lymphoid cell trafficking and immune responses. However, their importance in lymphoid reconstitution and function, studied by antibody blockade or in genetic models of chimeric animals with alpha4(KO) embryonic stem (ES) cells, competitive repopulation experiments with fetal liver(KO) cells, or in beta1/beta7 doubly-deficient mice has yielded disparate conclusions. To study the role of alpha4 integrin (alpha4beta1, alpha4beta7) during adult life, we transplanted lethally irradiated Rag2(-/-) mice with alpha4(Delta/Delta) or alpha4(f/f) adult bone marrow (BM) cells and evaluated recipients at several points after transplantation. Lymphomyeloid repopulation (8 months later) was entirely donor-derived in all recipients, and novel insights regarding lymphoid reconstitution and function were revealed. Thymic repopulation was impaired in all alpha4(Delta/Delta) recipients, likely because of homing defects of BM-derived progenitors, although a role of alpha4 integrin in intrathymic expansion/maturation of T cells cannot be excluded; reconstitution of gut lymphoid tissue was also greatly diminished because of homing defects of alpha4(Delta/Delta) cells; impaired immunoglobulin (Ig) M and IgE, but normal IgG responses were seen, suggesting compromised initial B-/T-cell interactions, whereas interferon-gamma production from ovalbumin-stimulated cells was increased, possibly reflecting a bias against Th2 stimulation. These data complement previous observations by defending the role of alpha4 integrin in thymic and gut lymphoid tissue homing, and by strengthening evidence of attenuated B-cell responses in alpha4-deficient mice.