Jonathan M. Green, M.D.
Pulmonary & Critical Care Medicine
Pathology and Immunology
The focus of my laboratory is to understand the role of accessory molecules on the surface of T lymphocytes in modulating the T cells response to antigen, and how these proteins influence susceptibility to disease. T cell recognition of antigen occurs through the interaction of the T cell receptor with an antigen-MHC complex. However, accessory proteins play critical roles in modulating both the initial responses to antigen as well differentiation into phenotypically distinct effector cells.
The importance of CD28 in T cell activation has been well documented; however, the mechanism by which CD28 regulates T cells remains controversial. We are currently exploring the biochemical basis for CD28 function using CD28-deficient mice and "CD28 knock-in" expressing specific mutant forms of CD28, which provide for the ability to determine the precise determinants of CD28 function both in vitro and in vivo. In addition, therapeutics have been developed that manipulate costimulatory pathways. We have identified a novel pathway by which engagement of B7 proteins by CTLA4Ig leads to a CD28-independent, NO/Treg/TGFb dependent inhibition of effector T cell responses.
Additional members of the B7:CD28 family have been shown to inhibit T cell function. Thus, both the intiation and termination of T cell directed immune responses are regulated by this family of receptors. New studies in the lab are directed at elucidating how the balance of these signals determine the outcome of inflammation in vivo.
Another major area of interest in the lab is the immune response to sepsis. Sepsis is the result of an uncontrolled inflammatory response to infection. Often, patients with sepsis develop an immunosuppressed condition which renders them susceptible to nosocomial infections. These infections are a major cause of morbidity and mortality. In collaborative studies with other Washington University researchers, we are actively engaged in studying the cellular and molecular mechanisms that result in immune suppression in sepsis.
Deppong, C.M., Bricker, T.L., Rannals, B.D., Van Rooijen, N.. Shieh, C-S and Green, J.M., 2013 CTLA4Ig inhibits effector T cells through regulatory T cells and TGFb. J. Immunol. In press
Parulekar, A.D., Boomer, J.S., Patterson, B.M., Yin-Declue, H., Deppong, C.M., Wilson, B.S., Jarjour, N.N., Castro M. and Green J.M. 2013., A randomized, controlled trial to evaluate inhibition of T cell costimulation in allergen induced airway inflammation. Amer J Resp Crit Care Med. 187:494-501
Boomer, J.S., To, K., Chang, K.C., Takasu, O., Osborne, D.F., Walton, A.H., Bricker, T.L., Jarman, S.D., Kreisel, D., Krupnick, A.S., Srivastava, A., Swanson, P.E., Green, J.M. and Hotchkiss, R.S. 2011. Immunosuppression in patients dying of sepsis and multiple organ failure. JAMA 306:2594-2605
Deppong, C.M. Parulekar, A., Boomer, J.S., Bricker, T.L. and Green, J.M. 2010. CTLA4Ig inhibits allergic airway inflammation by a novel CD28-independent, nitric oxide synthase dependent mechanism. Eur. J. Immunol. 40 (7):1985-1994
Dodson, L.F., Boomer, J.S., Deppong, C.M., Shah, D.D., Sim, J., Bricker, T.L., Russell, J.H. and Green, J.M., 2009 Targeted knockin mice expressing mutations of CD28 reveal an essential pathway for costimulation. Mol Cell Biol 29:3710-3721
Friend LD, Shah DD, Deppong C, et al. A dose dependent requirement for the proline motif of CD28 in cellular and humoral immunity revealed by a targeted knockin mutant. J Exp Med. 2006 Sep 4;203(9):2121-33. Epub 2006 Aug 14.
Deppong C, Juehne TI, Hurchla M, et al. Cutting Edge: B and T lymphocyte attenuator and programmed death receptor-1 inhibitory receptors are required for termination of acute allergic airway inflammation. J Immunol 2006 176:3909-3103.
Kimzey SL, Liu P and Green JM. Requirement for CD28 in the effector phase of allergic airway inflammation. J Immunol 2004 173:632-640.
Savage NDL, Kimzey SL, Bromley SK et al. Polar redistribution of the sialoglycoprotein CD43, implications for T cell function. J Immunol 2002 168:3740-3746.
Burr JS, Savage NDL, Kimsey SL, et al. Cutting edge: Distinct motifs within CD28 regulate T cell proliferation and induction of Bcl-XL. J Immunol 2001 166:5331-5335.
Last Updated: 8/1/2013 4:24:15 PM