|Barbara A. Osborne
Professor of Veterinary and Animal Sciences, University of Massachusetts
Ph.D.: Stanford University School of Medicine
Immunoglobulin Gene Diversification; Induction of Apoptosis in Lymphocytes
My laboratory studies two aspects of lymphocyte development and diversification. The production of a diverse repertoire of immunoglobulin molecules is of paramount importance to the maintenance of a functional immune system. One project in my laboratory focuses on B cell development and mechanisms of generation of immunoglobulin diversity in cattle. Unlike mouse and human, species that generate diversity by the rearrangement of numerous gene segments, cattle appear to use a recombinational mechanism known as gene conversion to generate a diverse repertoire of immunoglobulin molecules.
In addition to this novel mechanism of generating diversity, B cell development in cattle appears to differ from that observed in mouse and human; B cell development occurs in the ileal Payer’s patch, a specialized lymphoid organ, rather than in the bone marrow. Experiments designed to elucidate the exact mechanisms of diversification and processes that regulate B cell development are ongoing.
Another area of active investigation in my laboratory is elucidation of the molecular events required for the induction of apoptosis in the mouse thymus. Negative selection (the removal of autoreactive T cells) occurs by an active cell death process known as apoptosis. To isolate genes that are required for this process, we constructed a cDNA library from dying thymocytes and isolated several genes that are induced or repressed during apoptosis. We have shown that several of these genes, such as p53 and nur77, are required for cell death. Using techniques such as yeast two-hybrid analysis, we are now asking how these genes mediate cell death in T cells. Our current focus is a broader understanding of the roles played by these critical genes during apoptosis.
Kindt, T.J., Goldsby R.A. and B.A. Osborne. 2006. Kuby Immunology, WH Freeman, NY, NY.
Minter, L. M.,, D. M. Turley, P. Das, H. M. Shin, I. Joshi, R. G. Lawlor, O. H. Cho, T. Palaga, S. Gottipati, J. C. Telfer, L. Kostura, A. H. Fauq, K. Simpson, K. A. Such, L. Miele, T. E. Golde, S. D. Miller and B. A. Osborne. 2005. g-secretase inhibitors block in vivo and in vitro Th1 polarization by preventing Notch upregulation of t-bet . Nature Immunology, 6:680-8.
Shin, HM, Minter LM, Cho OH, Gottipati, S, Fauq AH, Golde TE, Sonenshein GE and BA Osborne 2005. Notch1 Augments NF- kB Activity by Facilitating its Nuclear Retention. EMBO J. 25:129-38.
Laws, A. and B.A. Osborne. 2004. p53 regulates thymic Notch1 activation.
Palaga, T., Miele, L, Golde, TE and BA Osborne. 2003. Notch-1 is required for the proliferation of peripheral T cells and IFN g production in CD8 T cells. J. Immunol. 171:3019-3024.
Minter, L. M. and B.A. Osborne (2003) Cell death in the thymus-it's all a matter of contacts. Seminars in Immunol. 15:135-144.
Tonomura, N., McLaughlin, K., Grimm, LM, Goldsby, RA and BA Osborne. 2003. Glucocorticoid-induced apoptosis of thymocytes:Requirement of proteasome-dependent mitochondrial activity. J. Immunol, 170(5):2469-78.
Palaga T., and B. Osborne (2002) The 3D's of apoptosis: death, degradation and DIAPs. Nat. Cell Biol. 4:E149-51 PubMed Abstract
Kuroiwa Y., Kasinathan P., Choi Y.J., Naeem R., Tomizuka K., Sullivan E.J., Knott J.G., Duteau A., Goldsby R.A., Osborne B.A., Ishida I. and J.M. Robl (2002) Cloned transchromosomic calves producing human immunoglobulin. Nat Biotechnol. 20(9):889-94 PubMed Abstract
Weijzen S., Braid E., Mehta R., Jonkheer S., Zlobin A., Osborne B.A., Gottipati S., Aster J., Hahn W.C., Kast M., and L. Miele (2002) Activation of Notch-1 signalling maintains the neoplastic phenotype in Ras-transformed cells. Nature Medicine 8:979-986 PubMed Abstract
Collas, P., R. Cline, H. B. Landsverk, W. R. Hein, R. A. Goldsby, B. A. Osborne and T. Landsverk (2002). "DNA-containing extracellular 50-nm particles in the ileal Peyer's patch of sheep." Eur J Cell Biol 81(2): 69-76.
Jeong, Y., B. A. Osborne and R. A. Goldsby (2001). "Early Vlambda diversification in sheep." Immunology 103(1): 26-34.
Valavanis, C., Y. Hu, Y. Yang, B. A. Osborne, S. Chouaib, L. Greene, J. D. Ashwell and L. M. Schwartz (2001). "Model cell lines for the study of apoptosis in vitro." Methods Cell Biol 66: 417-36.
Osborne, B. A. (2000). "Transcriptional control of T cell development." Curr Opin Immunol 12(3): 301-6.
Grimm, L. M. and B. A. Osborne (1999). "Apoptosis and the proteasome." Results Probl Cell Differ 23: 209-28.
Jehn, B. M., W. Bielke, W. S. Pear and B. A. Osborne (1999). "Cutting edge: protective effects of notch-1 on TCR-induced apoptosis." J Immunol 162(2): 635-8.
Lucier, M. R., R. E. Thompson, J. Waire, A. W. Lin, B. A. Osborne and R. A. Goldsby (1998). "Multiple sites of V lambda diversification in cattle." J Immunol 161(10): 5438-44.
Osborne, B.A. and L. Miele (1999) Notch and the immune system. Immunity 11:653-663
Miele, L. and B.A. Osborne (1999) Arbiter of differential and death: Notch signaling meets apoptosis. J Cell Physiol. 181(3):393-409
Morgan, G., Smith S.W., Pak, J., Marshak-Rothstein, A., Fissore, R. and B. A. Osborne. (1999) Characterization of a mutant T cell line with defects in TCR-mediated apoptosis. Cell Death & Differen. 6:36-47.