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

Objective α4 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 α4KO embryonic stem (ES) cells, competitive repopulation experiments with fetal liverKO cells, or in β1/β7 doubly-deficient mice has yielded disparate conclusions. Materials and Methods To study the role of α4 integrin (α4β1, α4β7) during adult life, we transplanted lethally irradiated Rag2–/– mice with α4Δ/Δ or α4f/f adult bone marrow (BM) cells and evaluated recipients at several points after transplantation. Results 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 α4Δ/Δ recipients, likely because of homing defects of BM-derived progenitors, although a role of α4 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 α4Δ/Δ cells; impaired immunoglobulin (Ig) M and IgE, but normal IgG responses were seen, suggesting compromised initial B-/T-cell interactions, whereas interferon-γ production from ovalbumin-stimulated cells was increased, possibly reflecting a bias against Th2 stimulation. Conclusion These data complement previous observations by defending the role of α4 integrin in thymic and gut lymphoid tissue homing, and by strengthening evidence of attenuated B-cell responses in α4-deficient mice.