Advertisement

Role of Integrin α4 (VLA – Very Late Antigen 4) in Lymphopoiesis by Short- and Long-Term Transplantation Studies in Genetic Knockout Model of Mice

  • Ena Ray Banerjee
Chapter

Abstract

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 liver KO cells, or in b1/b7 doubly deficient mice has yielded disparate conclusions.

Materials and Methods. To study the role of α4 integrin (α4b1, α4b7) 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-g 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.

Keywords

Donor Cell Recipient Mouse Lymphocyte Trafficking Hematopoietic Reconstitution Antibody Blockade 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    Luster AD, Alon R, von Andrian UH. Immune cell migration in inflammation: present and future therapeutic targets. Nat Immunol. 2005;6:1182–90.PubMedCrossRefGoogle Scholar
  2. 2.
    Brakebusch C, Bouvard D, Stanchi F, Sakai T, Fassler R. Integrins in invasive growth. J Clin Invest. 2002;109:999–1006.PubMedGoogle Scholar
  3. 3.
    Hynes RO. Integrins: bidirectional, allosteric signaling machines. Cell. 2002;110:673–87.PubMedCrossRefGoogle Scholar
  4. 4.
    Berlin C, Berg EL, Briskin MJ, et al. Alphα4beta7 integrin mediates lymphocyte binding to the mucosal vascular address in MAdCAM-1. Cell. 1993;74:185–95.PubMedCrossRefGoogle Scholar
  5. 5.
    Rose DM. The role of the alphα4 integrin-paxillin interaction in regulating leukocyte trafficking. Exp Mol Med. 2006;38:191–5.PubMedCrossRefGoogle Scholar
  6. 6.
    Mora JR, von Andrian UH. T-cell homing specificity and plasticity: new concepts and future challenges. Trends Immunol. 2006;27:235–43.PubMedCrossRefGoogle Scholar
  7. 7.
    Scimone ML, Aifantis I, Apostolou I, von Boehmer H, von Andrian UH. A multistep adhesion cascade for lymphoid progenitor cell homing to the thymus. PNAS. 2006;103:7006–11.PubMedCrossRefGoogle Scholar
  8. 8.
    Schmeissner PJ, Xie H, Smilenov LB, Shu F, Marcantonio EE. Integrin functions play a key role in the differentiation of thymocytes in vivo. J Immunol. 2001;67:3715–24.Google Scholar
  9. 9.
    Halin C, Scimone ML, Bonasio R, et al. The S1P-analog FTY720 differentially modulates T-cell homing via HEV: T-cell-expressed S1P1 amplifies integrin activation in peripheral lymph nodes but not in Peyer patches. Blood. 2005;106:1314–22.PubMedCrossRefGoogle Scholar
  10. 10.
    Arroyo AG, Yang JT, Rayburn H, Hynes RO. Differential requirements for alphα4 integrins during fetal and adult hematopoiesis. Cell. 1996;85:997–1108.PubMedCrossRefGoogle Scholar
  11. 11.
    Bell E, Sparshott S, Ager A. Migration pathways of CD4 T cell subsets in vivo: the CD45RC- subset enters the thymus via alpha 4 integrin- VCAM-1 interaction. Int Immunol. 1995;7:1861–71.PubMedCrossRefGoogle Scholar
  12. 12.
    Gribi R, Hook L, Ure J, Medvinsky A. The differentiation program of embryonic definitive hematopoietic stem cells is largely alphα4 integrin independent. Blood. 2006;108:501–9.PubMedCrossRefGoogle Scholar
  13. 13.
    Bungartz G, Stiller S, Bauer M, et al. Adult murine hematopoiesis can proceed without beta1 and beta7 integrins. Blood. 2006;108:1857–64.PubMedCrossRefGoogle Scholar
  14. 14.
    Scott L, Priestley GV, Papayannopoulou T. Deletion of alphα4 integrins from adult hematopoietic cells reveals roles in homeostasis, regeneration, and homing. Mol Cell Biol. 2003;23:9349–60.PubMedCrossRefGoogle Scholar
  15. 15.
    Priestley GV, Scott LM, Ulyanova T, Papayannopoulou T. Lack of alphα4 integrin expression in stem cells restricts competitive function and self-renewal activity. Blood. 2006;107:2959–67.PubMedCrossRefGoogle Scholar
  16. 16.
    Priestley GV, Ulyanova T, Papayannopoulou T. Sustained alterations in biodistribution of stem/ progenitor cells in Tie2cre + alphα4f/f mice are hematopoietic cell autonomous. Blood. 2007;109:109–11.PubMedCrossRefGoogle Scholar
  17. 17.
    Ulyanova T, Scott L, Priestley G, et al. VCAM-1 expression in adult hematopoietic and nonhematopoietic cells is controlled by tissue inductive signals and reflects their developmental origin. Blood. 2005;106:86–94.PubMedCrossRefGoogle Scholar
  18. 18.
    McAdam AJ, Greenwald RJ, Levin MA, et al. ICOS is critical for CD40-mediated antibody class switching. Nature. 2001;409:102–5.PubMedCrossRefGoogle Scholar
  19. 19.
    Prockop SE, Petrie HT. Regulation of thymus size by competition for stromal niches among early t cell progenitors. J Immunol. 2004;173:1604–11.PubMedGoogle Scholar
  20. 20.
    Banerjee ER, Jiang Y, Henderson JWR, Scott LM, Papayannopoulou T. alphα4 and beta2 integrins have nonredundant roles for asthma development, but for optimal allergen sensitization only alphα4 is critical. Exp Hematol. 2007;35:605–17.PubMedCrossRefGoogle Scholar
  21. 21.
    Issekutz T. Inhibition of in vivo lymphocyte migration to inflammation and homing to lymphoid tissues by the TA-2 monoclonal antibody. A likely role for VLA-4 in vivo. J Immunol. 1991;147:4178–84.PubMedGoogle Scholar
  22. 22.
    Arroyo AG, Taverna D, Whittaker CA, et al. In vivo roles of integrins during leukocyte development and traffic: insights from the analysis of mice chimeric for alpha5, alphav, and alphα4 integrins. J Immunol. 2000;165:4667–75.PubMedGoogle Scholar
  23. 23.
    Arroyo AG, Yang JT, Rayburn H, Hynes RO. Alphα4 integrins regulate the proliferation/differentiation balance of multilineage hematopoietic progenitors in vivo. Immunity. 1999;11:555.PubMedCrossRefGoogle Scholar
  24. 24.
    Rossi FMV, Corbel SY, Merzaban JS, et al. Recruitment of adult thymic progenitors is regulated by P-selectin and its ligand PSGL-1. Nat Immunol. 2005;6:626–34.PubMedCrossRefGoogle Scholar
  25. 25.
    Parmo-Cabanas M, Garcia-Bernal D, Garcia-Verdugo R, Kremer L, Marquez G, Teixido J. Intracellular signaling required for CCL25- stimulated T cell adhesion mediated by the integrin alphα4 beta1. J Leukoc Biol. 2007;82:380–91.PubMedCrossRefGoogle Scholar
  26. 26.
    Ara T, Itoi M, Kawabata K, et al. A role of CXC chemokine ligand 12/stromal cell-derived factor-1/pre-B cell growth stimulating factor and its receptor CXCR4 in fetal and adult T cell development in vivo. J Immunol. 2003;170:4649–55.PubMedGoogle Scholar
  27. 27.
    Plotkin J, Prockop SE, Lepique A, Petrie HT. Critical role for CXCR4 signaling in progenitor localization and T cell differentiation in the postnatal thymus. J Immunol. 2003;171:4521–7.PubMedGoogle Scholar
  28. 28.
    Crisa L, Cirulli V, Ellisman MH, et al. Cell adhesionand migration are regulated at distinct stages of thymic T cell development: the roles of fibronectin, VLA4, and VLA5. J Exp Med. 1996;184:215–28.PubMedCrossRefGoogle Scholar
  29. 29.
    Sitnicka E, Buza-Vidas N, Ahlenius H, et al. Critical role of FLT3 = ligand in IL-7 receptor-independent T lymphopoiesis and regulation of lymphoid-primed multipotent progenitors. Blood. 2007;110:2955–64.PubMedCrossRefGoogle Scholar
  30. 30.
    Boyd RL, Tucek CL, Godfrey DI, et al. The thymic microenvironment. Immunol Today. 1993;14:445–59.PubMedCrossRefGoogle Scholar
  31. 31.
    van Ewijk W, Shores EW, Singer A. Crosstalk in the mouse thymus. Immunol Today. 1994;15:214–17.PubMedCrossRefGoogle Scholar
  32. 32.
    Hamann A, Andrew DP, Jablonski-Westrich D, Holzmann B, Butcher EC. Role of alpha 4-integrins in lymphocyte homing to mucosal tissues in vivo. J Immunol. 1994;152:3282–93.PubMedGoogle Scholar
  33. 33.
    Xu B, Wagner N, Pham LN, et al. Lymphocyte homing to bronchus associated lymphoid tissue (BALT) is mediated by L-selectin/PNAd, alphα4beta1 integrin/VCAM-1, and LFA-1 adhesion pathways. J Exp Med. 2003;197:1255–67.PubMedCrossRefGoogle Scholar
  34. 34.
    Berlin-Rufenach C, Otto F, Mathies M, et al. Lymphocyte migration in lymphocyte function-associated antigen (LFA)-1-deficient mice. J Exp Med. 1999;189:1467–78.PubMedCrossRefGoogle Scholar
  35. 35.
    Finke D, Kraehenbuhl J-P. Formation of Peyer’s patches. Curr Opin Genet Dev. 2001;11:561–7.PubMedCrossRefGoogle Scholar
  36. 36.
    Finke D, Acha-Orbea H, Mattis A, Lipp M, Kraehenbuhl JP. CD4 + CD3- cells induce Peyer’s patch development: role of alphα4- beta1 integrin activation by CXCR5. Immunity. 2002;17:363–73.PubMedCrossRefGoogle Scholar
  37. 37.
    Maillard I, Schwarz BA, Sambandam A, et al. Notch-dependent T-lineage commitment occurs at extrathymic sites following bone marrow transplantation. Blood. 2006;107:3511–19.PubMedCrossRefGoogle Scholar
  38. 38.
    Koni PA, Joshi SK, Temann U-A, Olson D, Burkly L, Flavell RA. Conditional vascular cell adhesion molecule 1 deletion in mice: impaired lymphocyte migration to bone marrow. J Exp Med. 2001;193:741–54.PubMedCrossRefGoogle Scholar
  39. 39.
    Leuker CE, Labow M, Muller W, Wagner N. Neonatally induced inactivation of the vascular cell adhesion molecule 1 gene impairs B cell localization and T cell-dependent humoral immune response. J Exp Med. 2001;193:755–68.PubMedCrossRefGoogle Scholar
  40. 40.
    Barreiro O, de la Fuente H, Mittelbrunn M, Sanchez-Madrid F. Functional insights on the polarized redistribution of leukocyte integrins and their ligands during leukocyte migration and immune interactions. Immunol Rev. 2007;218:147–64.PubMedCrossRefGoogle Scholar
  41. 41.
    Carrasco YR, Batista FD. B-cell activation by membrane-bound antigens is facilitated by the interaction of VLA-4 with VCAM-1. EMBO J. 2006;25:889–99.PubMedCrossRefGoogle Scholar
  42. 42.
    Thai T-H, Calado DP, Casola S, et al. Regulation of the germinal center response by microRNA-155. Science. 2007;316:604–8.PubMedCrossRefGoogle Scholar

Published in

  1. Banerjee ER, Latchman YL, Jiang Y, Priestley GV, Papayannopoulou T. Distinct changes in adult lymphopoiesis in Rag2−/− mice fully reconstituted by α4-deficinet adult bone marrow cells. Exp Hematol. 2008;36(8):1004–13.PubMedCrossRefGoogle Scholar

Copyright information

© Springer India 2014

Authors and Affiliations

  • Ena Ray Banerjee
    • 1
  1. 1.Immunology & Regenerative Medicine Research UnitUniversity College of Science, Technology and AgricultureKolkataIndia

Personalised recommendations