Douglas A. Steeber University of Wisconsin-Milwaukee

Douglas A. Steeber
Associate Professor
UWM Chancellor's Scientist

Ph.D., University of Wisconsin - Madison
1995
Postodoctoral Fellow
Duke University Medical Center
1997
Assistant Research Professor
Duke University Medical Center
2003

Office: Lapham N211
Phone: 414-229-4373
FAX: 414-229-3926
Email: steeber@uwm.edu
Electronic Reserve
Materials:
Immunology

Research Interests

The body's defense against invading pathogens is dependent on a group of cells called white blood cells or leukocytes. The migration of leukocytes from the blood into tissues at sites of infection is crucial for this defense, called an immune response. Leukocyte migration occurs following a complex series of interactions with endothelial cells that line blood vessels. These interactions are mediated by multiple adhesion molecules expressed on the surface of leukocytes and endothelial cells. One type of leukocyte, the lymphocyte, migrates continuously from the blood stream, into lymphoid tissues, and then back into the blood in a process called recirculation. The process of lymphocyte recirculation involves the migration of lymphocytes across specialized high endothelial venules (HEV) present within lymph nodes, and it is within these tissues that lymphocytes encounter trapped antigens such as bacterial proteins (Fig. 1). This relentless surveillance of secondary lymphoid tissues by lymphocytes is an essential component of the immune response.

Two adhesion molecules, L-selectin and b7 integrin, are dominant in regulating lymphocyte migration. Interestingly, in some tissues L-selectin and b7 integrin function together to regulate lymphocyte migration, while other tissues are uniquely regulated by one molecule or the other. L-selectin also facilitates the interactions of leukocytes with the vascular endothelium at sites of tissue injury or inflammation. One area of interest in the lab is to define the differential roles of these adhesion molecules by examining the immune responses of mice made deficient in L-selectin and/or b7 integrin by gene targeting (Fig. 2).

These adhesion molecule deficient lines of mice have also been crossed with mouse strains used in the study of human autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus (i.e., SLE or lupus). Current studies are examining the role of these adhesion molecules in the onset, progression and severity of these diseases. The overall goal of these studies is to develop novel immunization schemes that maximize immune responses, target immune responses to desired sites, and identify potential targets for the development of therapeutics to block unregulated, pathological leukocyte migration.

Other studies in the lab continue to make use of a panel of novel monoclonal antibodies directed against L-selectin that were previously generated. These studies shown that L-selectin is a potent signaling molecule for leukocytes. Biochemical and mutational analyses have determined that only ligation of conserved ligand binding epitopes of L-selectin generate transmembrane signals and that the cytoplasmic domain is required for this signaling to occur. The signaling pathway(s) activated through ligation of L-selectin as well as the biological significance of this signaling is currently under investigation. A similar ongoing line of investigation concerns cross-talk between adhesion molecules and chemoattractant receptors. These studies have clearly demonstrated that L-selectin is rapidly phosphorylated following activation of chemoattractant receptors and suggest that this is involved in up-regulation of L-selectin binding activity. Current investigations are looking at modulation of chemoattractant receptor function following signaling through ligation of L-selectin. These studies are key to our understanding the complex interactions between these molecules that must take place to allow leukocyte migration to occur at sites of inflammation.

Selected Publications

    1.  Venturi, GM, Conway, RM, Steeber, DA, Tedder, TF.  CD25+CD4+ regulatory T cell migration requires L-selectin expression: L-selectin transcriptional regulation balances constitutive receptor turnover.  Journal of Immunology  2007; 178: 291-300.

    2.  Kodera, M, Subramanian, H, Conway, RM, Grailer, JJ, Karalewitz, AP-A, Steeber, DA.  Tracking the immune response using correlative microscopic, flow cytometric and chemotaxis assays.  Microscopy and Microanalysis  2006; 12: 30-31.

    3.  Horikawa, M, Fujimoto, M, Hasegawa, M, Matsushita, T, Hamaguchi, Y, Kawasuji, A, Matsushita, Y, Fujita, T, Ogawa, F, Takehara, K, Steeber, DA, Sato, S.  E- and P-selectins synergistically inhibit bleomycin-induced pulmonary fibrosis.  American Journal of Pathology  2006; 169: 740-749.

    4.  Yamada, M, Yanaba, K, Hasegawa, M, Matsushita, Y, Horikawa, M, Komura, K, Matsushita, T, Kawasuji, A, Fujita, T, Takehara, K, Steeber, DA, Tedder, TF, Sato, S.  Regulation of local and metastatic host-mediated anti-tumour mechanisms by L-selectin and intercellular adhesion molecule-1.  Clinical and Experimental Immunology  2006; 143: 216-227.

    5.  Kawasuji, A, Hasegawa, M, Horikawa, M, Fujita, T, Matsushita, Y, Matsushita, T, Fujimoto, M, Takehara, K, Steeber, DA, Tedder, TF, Sato, S.  L-selectin and intercellular adhesion molecule-1 regulate the development of concanavalin A-induced liver injury.  Journal of Leukocyte Biology.  2006; 79: 696-705. 

    6.  Fadel, SA, Cowell, L, Cao, S, Ozaki, DA, Kepler, TB, Steeber, DA, Sarzotti, M.  Neonate-primed CD8+ memory cells rival adult-primed memory cells in antigen-driven expansion and anti-viral protection.  International Immunology.  2006; 18: 249-257.

    7.  Peng, Q, Yang, S, Charkowski, AO, Yap, M-N, Steeber, DA, Keen, NT, Yang, C-H.  Population behavior analysis of dspE and pelD regulation in Erwinia chrysanthemi 3937.  Molecular Plant-Microbe Interaction.  2006, 19: 451-457. 

    8.  Haas, KM, Poe, JC, Steeber, DA, Tedder, TF.  B-1a and B-1b cells exhibit distinct developmental requirements and have unique functional roles in innate and adaptive immunity to S. pneumoniae.  Immunity 2005; 23: 7-18. 

    9.  Steeber, DA, Venturi, GM, Tedder, TF.  A new twist to the leukocyte adhesion cascade: Intimate cooperation is key.  Trends in Immunology  2005; 26: 9-12.

    10. Uchida, J, Lee, Y, Hasegawa, M, Liang, Y, Bradney, A, Oliver, JA, Bowen, K, Steeber, DA, Haas, KM, Poe, JC, Tedder, TF.  Mouse CD20 expression and function.  International Immunology 2004; 16:119-129.

    11. Venturi, GM, Tu, L., Kadono, T, Khan, AI, Fujimoto, Y, Oshel, P, Bock, CB, Miller, AS, Albrecht, RM, Kubes, P, Steeber, DA, Tedder, TF.  Leukocyte migration is regulated by L-selectin endoproteolytic release.  Immunity 2003; 19: 713-724. 

    12. Komura, K, Hasegawa, M, Hamaguchi, Y, Saito, E, Kaburagi, Y, Yanaba, K, Kawara, S, Takehara, K, Seki, M, Steeber, DA, Tedder, TF, Sato, S.  UV light exposure suppresses contact hypersensitivity by abrogating endothelial ICAM-1 up-regulation at the elicitation site.  Journal of Immunology 2003; 171: 2855-2862. 

    13. Yanaba, K, Kaburagi, Y, Takehara, K, Steeber, DA, Tedder, TF, Sato, S.  Relative contributions of selectins and intercellular adhesion molecule-1 to tissue injury induced by immune complex deposition.  American Journal of Pathology  2003; 162: 1463-1473. 

    14. Shimada, Y, Hasegawa, M, Kaburagi, Y, Hamaguchi, Y, Komura, K, Saito, E, Takehara, K, Steeber, DA, Tedder, TF, Sato, S.  L-selectin or ICAM-1 deficiency reduces an immediate-type hypersensitivity response by preventing mast cell recruitment in repeated elicitation of contact hypersensitivity.  Journal of Immunology 2003; 170:4325-4334. 

    15. Haas, KM, Hasegawa, M, Steeber, DA, Poe, JC, Zabel, MD, Bock, CB, Karp, DR, Briles, DE, Weis, JH, Tedder, TF.  Complement receptors CD21/35 link innate and protective immunity during Streptococcus pneumoniae infection by regulating IgG3 antibody responses.  Immunity  2002; 17: 713-723. 

    16. Hamaguchi, Y, Nishizawa, Y, Yasui, M, Hasegawa, M, Kaburagi, Y, Komura, K, Nagaoka, T, Saito, E, Shimada, Y, Takehara, K, Kadono, T, Steeber, DA, Tedder, TF, Sato, S.  Intercellular adhesion molecule-1 and L-selectin regulate bleomycin-induced lung fibrosis. American Journal of Pathology  2002; 161: 1607-1618. 

    17. Kadono, T, Venturi, GM, Steeber, DA, Tedder, TF.  Leukocyte rolling velocities and migration are optimized by cooperative L-selectin and intercellular adhesion molecule-1 functions. Journal of Immunology  2002; 169: 4542-4550. 

    18. Tu, L, Poe, JC, Kadono, T, Venturi, GM, Bullard, DC, Tedder, TF, Steeber, DA.  A functional role for circulating mouse L-selectin in regulating leukocyte/endothelial cell interactions in vivo. Journal of Immunology  2002; 169: 2034-2043. 

    19. Fujimoto, Y, Tu, L, Miller, AS, Bock, C, Fujimoto, M, Doyle, C, Steeber, DA, Tedder, TF.  CD83 expression influences CD4+ T cell development in the thymus.  Cell  2002; 108: 755-767. 

    20. Dwir, O, Steeber, DA, Schwarz US, Camphausen, RT, Kansas, GS, Tedder, TF, Alon, R.  L-selectin dimerization enhances tether formation to properly spaced ligand.  Journal of Biological Chemistry  2002; 277: 21130-21139. 

    21. Kaburagi, Y, Hasegawa, M, Nagaoka, T, Shimada, Y, Hamaguchi, Y, Komura, K, Saito, E, Yanaba, K, Takehara, K, Kadono, T, Steeber, DA, Tedder, TF, Sato, S.  The cutaneous reverse arthus reaction requires intercellular adhesion molecule-1 and L-selectin expression. Journal of Immunology  2002; 168: 2970-2978. 

    22. Friedline, RH, Wong, CP, Steeber, DA, Tedder, TF, Tisch, R.  L-selectin is not required for T cell-mediated autoimmune diabetes. Journal of Immunology  2002; 168: 2659-2666. 

    23. Hasegawa, M, Fujimoto, M, Poe, JC, Steeber, DA, Tedder, TF.  CD19 can regulate B lymphocyte signal transduction independent of complement activation. Journal of Immunology  2001; 167: 3190-3200. 

    24. Hasegawa, M, Fujimoto, M, Poe, JC, Steeber, DA, Lowell, CA, Tedder, TF.  A CD19-dependent signaling pathway regulates autoimmunity in Lyn-deficient mice. Journal of Immunology  2001; 167: 2469-2478. 

    25. Fiscus, LC, Van Herpen, J, Steeber, DA, Tedder, TF, Tang, MLK.  L-selectin is required for the development of airway hyperresponsiveness but not airway inflammation in a murine model of asthma. Journal of Allergy and Clinical Immunology  2001; 107: 1019-1024. 

    26. Li, X, Tu, L, Murphy, PG, Kadono, T, Steeber, DA, Tedder, TF.  CHST1 and CHST2 sulfotransferase expression by vascular endothelial cells regulates shear-resistant leukocyte rolling via L-selectin.  Journal of Leukocyte Biology  2001; 69: 565-574. 

    27. Keramidaris, E, Merson, T, Steeber, DA, Tedder, TF, Tang, MLK.  L-selectin and ICAM-1 mediate lymphocyte migration to the inflamed airway/lung during an allergic inflammatory response in an animal model of asthma.  Journal of Allergy and Clinical Immunology  2001; 107: 734-738. 

    28. Leid, JG, Steeber, DA, Tedder, TF, Jutila, MA.  Antibody binding to a conformation-dependent epitope induces L-selectin association with the detergent-resistant cytoskeleton. Journal of Immunology  2001; 166: 4899-4907. 

    29. Steeber, DA, Tedder, TF.  Adhesion molecule cascades direct lymphocyte recirculation and leukocyte migration during inflammation.  Immunologic Research  2000; 22: 299-317.

    30. Inaoki, M, Sato, S, Shimada, Y, Kawara, S, Steeber, DA, Tedder, TF, Takehara, K.  Decreased expression levels of L-selectin on subsets of leukocytes and increased serum L-selectin in severe psoriasis.  Clinical and Experimental Immunology  2000; 122: 484-492. 

    31. Haribabu, B, Verghese, MW, Steeber, DA, Sellars, DD, Bock, CB, Snyderman, R.  Targeted disruption of the leukotriene B4 receptor in mice reveals its role in inflammation and platelet-activating factor-induced anaphylaxis.  Journal of Experimental Medicine  2000; 192: 433-438.

    32. Nagaoka, T, Kaburagi, Y, Hamaguchi, Y, Hasegawa, M, Takehara, K, Steeber, DA, Tedder, TF, Sato, S.  Delayed wound healing in the absence of intercellular adhesion molecule-1 or L-selectin expression. American Journal of Pathology  2000; 157: 237-247. 

    33. Wilcox, DA, Olsen, JC, Ishizawa, L, Bray, PF, French, DL, Steeber, DA, Bell, WR, Griffith, M, White, GC.  Megakaryocyte-targeted synthesis of the integrin b3-subunit results in the phenotypic correction of glanzmann's thrombasthenia.  Blood  2000; 95: 3645-3652. 

    34. Yan, Z-Q, Bolognesi, MP, Steeber, DA, Tedder, TF, Chen, L-E, Seaber, AV, Urbaniak, JR.  Blockade of L-selectin attenuates reperfusion injury in a rat model.  Journal of Reconstructive Microsurgery  2000; 16: 227-233. 

    35. Fujimoto, M, Bradney, AP, Poe, JC, Steeber, DA, Tedder, TF.  Modulation of B lymphocyte antigen receptor signal transduction by a CD19/CD22 regulatory loop.  Immunity  1999; 11: 191-200.

    36. Steeber, DA, Tang, MLK†, Green, NE, Zhang, X-Q, Sloane, JE, Tedder, TF.  Leukocyte entry into sites of inflammation requires overlapping interactions between the L-selectin and Intercellular adhesion molecule-1 pathways.  Journal of Immunology  1999; 163: 2176-2186. 

    37. Yadav, SS, Howell, DN, Steeber, DA, Harland, RC, Tedder, TF, Clavien, P-A.  P-selectin mediates reperfusion injury through neutrophil and platelet sequestration in the warm ischemic mouse liver.  Hepatology   1999; 29: 1494-1502. 

    38. Kanwar, S, Steeber, DA, Tedder, TF, Hickey, MJ, Kubes, P.  Overlapping roles for L-selectin and P-selectin in antigen-induced immune responses in the microvasculature.  Journal of Immunology  1999; 162: 2709-2716. 

    39. Robinson, LA, Tu, L, Steeber, DA, Preis, O, Platt, JL, Tedder, TF.  The role of adhesion molecules in human leukocyte attachment to porcine vascular endothelium:  Implications for xenotransplantation.  Journal of Immunology  1998; 161: 6931-6938.

    40. Steeber, DA, Tang, MLK, Zhang, X-Q, Müller, W, Wagner, N, Tedder, TF.  Efficient lymphocyte migration across high endothelial venules of mouse peyer's patches requires overlapping expression of L-selectin and b7 integrin.  Journal of Immunology  1998; 161: 6638-6647. 

    41. Mostaghel, EA, Riberdy, JM, Steeber, DA, Doyle, C.  Coreceptor-independent T cell activation in mice expressing MHC class II molecules mutated in the CD4 binding domain.  Journal of Immunology  1998; 161: 6559-6566. 

    42. Yadav, SS, Howell, DN, Gao, W, Steeber, DA, Harland, RC, Clavien, P-A.  L-selectin and ICAM-1 mediate reperfusion injury and neutrophil adhesion in the warm ischemic mouse liver.  American Journal of Physiology  1998; 275: G1341-G1352.

    43. Wagner, N, Löhler, J, Tedder, TF, Rajewsky, K, Müller, W, Steeber, DA.  L-selectin and b7 integrin synergistically mediate lymphocyte migration to mesenteric lymph nodes.  European Journal of Immunology  1998; 28: 3832-3839. 

    44. Fong, AM, Robinson, LA, Steeber, DA, Tedder, TF, Yoshie, O, Imai, T, Patel, DD.  Fractalkine and CX3CR1 mediate a novel mechanism of leukocyte capture, firm adhesion, and activation under physiologic flow.  Journal of Experimental Medicine  1998; 188: 1413-1419.

    45. Li, X, Steeber, DA, Tang, MLK, Farrar, MA, Perlmutter, RM, Tedder, TF.  Regulation of L-selectin-mediated rolling through receptor dimerization.  Journal of Experimental Medicine  1998; 188: 1385-1390. 

    46.  Kunkel, EJ, Ramos, CL, Steeber, DA, Müller, W, Wagner, N, Tedder, TF, Ley, K.  The roles of L-selectin, b7 integrins and P-selectin in leukocyte rolling and adhesion in high endothelial venules of peyer's patches.  Journal of Immunology  1998; 161: 2449-2456. 

    47. Steeber, DA, Campbell, MA, Basit, A, Ley, K, Tedder, TF.  Optimal selectin-mediated rolling of leukocytes during inflammation in vivo requires intercellular adhesion molecule-1 expression.  Proceedings of the National Academy of Science USA  1998; 95: 7562-7567. 

    48. Tang, MLK†, Steeber, DA†, Zhang X-Q, Tedder, TF.  Intrinsic differences in L-selectin expression levels affect T and B lymphocyte subset-specific recirculation pathways.  Journal of Immunology  1998; 160: 5113-5121. †Both authors contributed equally

    49. Davenpeck, KL, Steeber, DA, Tedder, TF, Bochner, BS.  P- and L-selectin mediate distinct but overlapping functions in endotoxin-induced leukocyte-endothelial interactions in the rat mesenteric microcirculation.  Journal of Immunology  1997; 159: 1977-1986. 

    50. Steeber, DA, Engel, P, Miller, AS, Sheetz, MP, Tedder, TF.  Ligation of L-selectin through conserved regions within the lectin domain activates signal transduction pathways and integrin function in human, mouse, and rat leukocytes.  Journal of Immunology  1997; 159: 952-963. 

    51. Tang, MLK, Hale, LP, Steeber, DA, Tedder, TF.  L-selectin is involved in lymphocyte migration to sites of inflammation in the skin:  Delayed rejection of allografts in L-selectin-deficient mice.  Journal of Immunology  1997; 158: 5191-5199.

    52. Haribabu, B, Steeber, DA, Ali, H, Richardson, RM, Snyderman, R, Tedder, TF.  Chemoattractant receptor-induced phosphorylation of L-selectin.  Journal of Biological Chemistry  1997; 272: 13961-13965. 

    53. Sato, S, Steeber, DA, Jansen, PJ, Tedder, TF.  CD19 expression levels regulate B lymphocyte development:  Human CD19 restores normal function in mice lacking endogenous CD19.  Journal of Immunology  1997; 158: 4662-4669. 

    54. Allport, JR, Ding, HT, Ager, A, Steeber, DA, Tedder, TF, Luscinskas, FW.  L-selectin shedding does not regulate human neutrophil attachment, rolling or transmigration across human vascular endothelium in vitro.  Journal of Immunology  1997; 158: 4365-4372. 

    55. Fryer, AD, Costello, RW, Lobb, RR, Tedder, TF, Steeber, DA, Bochner, BS.  Antibody to VLA-4, but not to L-selectin, protects neuronal M2 muscarinic receptors in antigen-challenged guinea pig airways.  Journal of Clinical Investigation  1997; 99: 2036-2044.

    56. Doyle, NA, Bhagwan, SD, Meek, BB, Kutkoski, GJ, Steeber, DA, Tedder, TF, Doerschuk, CM.  Neutrophil margination, sequestration and emigration in the lungs of L-selectin mutant mice.  Journal of Clinical Investigation  1997; 99: 526-533. 

    57. Steeber, DA, Green, NE, Sato, S, Tedder, TF.  Humoral immune responses in L-selectin deficient mice.  Journal of Immunology  1996; 157: 4899-4907. 

    58. Sato, S, Ono, N, Steeber, DA, Pisetsky, DS, Tedder, TF.  CD19 regulates B lymphocyte signaling thresholds critical for the development of B-1 lineage cells.  Journal of Immunology  1996; 157: 4371-4378. 

    59. Steeber, DA, Green, NE, Sato, S, Tedder, TF.  Lymphocyte migration in L-selectin deficient mice: altered subset migration and aging of the immune system.  Journal of Immunology  1996; 156: 1096-1106.

    60. Sato, S, Steeber, DA, Tedder, TF.  The CD19 signal transduction molecule is a response regulator of B lymphocyte differentiation.  Proceedings of the National Academy of Science USA  1995; 92: 11558-11562. 

    61. Tedder, TF, Steeber, DA, Chen, A, Engel, P.  The selectins: vascular adhesion molecules.  FASEB J.  1995; 9:866-873.

    62. Tedder, TF, Steeber, DA, Pizcueta, P.  L-selectin deficient mice have imparied leukocyte recruitment into inflammatory sites.  Journal of Experimental Medicine  1995; 181: 2259-2264. 

    63. Bolger, R, Steeber, DA, Suttie, J, Albrecht, R.  Tissue preparation for 1 MeV observation:  Chemical fixation and embedding vs. high pressure freeze fixation, freeze substitution and cold temperature embedding.  Midwest Microscopy  1993; 22:6-9. 

    64. Steeber, DA, Butzow, J, Lutz, L, Albrecht, RM.  Immunotoxicity of organophosphates:  Inhibition of cell surface antigen expression and cell differentiation.  Midwest Microscopy  1991;21:27-29. 

    65. Hodde, KC, Steeber, DA, Albrecht, RM.  Advances in corrosion casting methods.  Scanning Microscopy  1990; 4: 693-704. 

    66. Steeber, DA, Erickson, CM, Hodde, KC, Albrecht, RM.  Vascular changes in popliteal lymph nodes due to antigen challenge in normal and lethally irradiated mice.  Scanning Microscopy  1987; 1: 831-839.

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