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Carver
College of Medicine Distinguished Professor of Microbiology and
Internal Medicine
Director
of the Interdisciplinary Graduate Immunology Program
University
of Michigan, 1983
Recent
Publications:
Munroe, M.E., and G.A. Bishop. 2007. A costimulatory function for T cell CD40. J Immunol 178:671-682.
Xie, P., B.S. Hostager, M.E. Munroe, C.R. Moore, and G.A. Bishop. 2006. Cooperation between TRAFs 1 and 2 in CD40 signaling. J Immunol 176:5388-5400.
Moore, C.R., and G.A. Bishop. 2005. Differential regulation of CD40-mediated TRAF degradation in B lymphocytes. J Immunol 175:3780-3789.
See
complete publications list at PubMed
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Molecular mechanisms
of B lymphocyte activation by normal and viral oncogenic receptors
We are interested in the molecular mechanisms which underlie the processes of B lymphocyte activation in normal immunity, autoimmunity, and malignancy. We are particularly interested in how signals delivered via B cell transmembrane molecules regulate these events, and our particular area of focus is antigen-specific, T cell-B cell interactions.
The following is a sample of some projects ongoing in the lab -
A) Molecular mechanisms of signaling by TNFR superfamily receptors. The following are some of the question we are addressing.
1. What is the role of TRAF degradation in regulation of receptor signaling? Ligand binding to many TNFR superfamily receptors induces recruitment of TNFR associated factors (TRAFs) to membrane microdomains (rafts). For certain receptors and TRAFs, this is followed by degradation of the recruited TRAF molecules. Blocking this degradation can result in amplified and sustained receptor signaling, indicating that this is an important regulatory mechanism. However, receptor-induced TRAF degradation is not universally seen, including in signaling by the oncogenic CD40 mimic made by the Epstein Barr virus, LMP1. We are examining the factors regulating TRAF degradation, and its consequences in regulation of signaling cascades.
2. What is the function of TRAF5 in B and T cell activation? The function of TRAF5 in TNFR superfamily receptor signaling is not well understood. We now wish to extend our studies to TRAF5. Using TRAF5-/- mice, we are currently examining the importance and specific roles of TRAF5 in both humoral and cell-mediated immunity, and in particular in signaling by CD40 and CD27.
3. How does TRAF3 contribute to regulation of T and B cell functions? Although numerous reports have focused upon how the widely used TRAF2 molecule contributes to positive signals by CD40 and most other TNFR family molecules, little has been known about the functions of TRAF3, which shares a highly overlapping receptor binding site with TRAF2. It is now clear from work performed by our group and others that TRAF3 can play diverse, even sharply contrasting roles in signaling by different receptors, including both the TNFR superfamily, LMP1, and the toll-like receptors (TLR) of the innate immune system.. To explore further the biological function of this understudied TRAF, we are employing a conditional TRAF3 deficient mouse strain we have recently produced, together with TRAF3-deficient cell lines, to understand the roles played by TRAF3 in B and T cell activation.
B) What is the mechanism of LMP1 signaling to the B cell? How does this promote lymphomagenesis and autoreactivity?
A protein produced by EBV in latently infected cells, LMP1, also binds TRAF2 and TRAF3 molecules, although LMP1 is not a member of the TNFR family. LMP1 is the EBV protein mainly responsible for EBV-mediated B cell transformation and lymphomagenesis, and this function appears to require the TRAF-binding region of its cytoplasmic domain. We have found that LMP1 expression stimulates many of the same effects in B cells as does CD40 (surface molecule upregulation, NF-κ B activation, Ig secretion, protection from apoptosis, IL-6 secretion), and using a hybrid molecule, find that the carboxy terminus of LMP1 is sufficient for these functions. Use of CD40-LMP1 hybrid molecules revealed that LMP1 signals are amplified and sustained, compared to the CD40 signals they mimic. Interestingly, following raft recruitment, CD40 association stimulates degradation of TRAFs 2 and 3, while LMP1 does not. LMP1 signals normally in TRAF2-deficient B cells, but its signaling is strongly impaired in TRAF3-/- B cells, in marked contrast to CD40 signals. We are examining LMP1 signals to B cells in further detail. Our studies make use of complementary experimental approaches, including cell lines, an LMP1 transgenic mouse strain we have produced, and fresh human tumor samples. We are currently focusing on how CD40 signals to an LMP1-expressing cell impact the LMP1 signals, the role of IL-6 in the autoreactivity promoted by LMP1 signals, and how LMP1 expression interacts with other signals that predispose to malignancy and autoimmunity.
C) How do adaptive and innate receptor signals interact in B cells? This new project is examining the interactions between Toll-like receptors and adaptive immune receptors in B cell activation.
1. What are the molecular mechanisms by which signals via adaptive and innate receptors interact? We hypothesize that distinct signaling pathways will influence ultimate outcome. This is being examined by measuring relevant cellular functions, then examining specific early molecular events that preliminary data indicate are key to these functions. Understanding gained should permit more precise design of antigen-adjuvant combinations for safe, effective vaccines in a variety of clinical and public health settings.
2. What are the effects of interactive signals between adaptive and innate receptors on the function of B cells as antigen-presenting cells (APC)? We hypothesize that interactions between these receptor types will enhance the APC ability of B lymphocytes. We are examining this question in mouse models, using adoptive transfer and immunization. This information will allow design of vaccines that maximize the efficacy of B cell activation, not only to produce antibodies, but also to activate cellular responses as APC.
3. How is function of innate receptors for microbial nucleic acids regulated by their structure, and how may sequential or concomitant engagement of distinct receptors for microbial nucleic acids influence immune reactivity? We are testing the hypothesis that differences between structures of TLR7 and TLR8, as well as structural differences between mouse and human TLR8, will regulate key functional features of these receptors in immune stimulation. A second hypothesis to be tested is that prior signals through TLR7/8 may alter the subsequent cellular response to TLR9 signals, possibly contributing to the increased susceptibility to bacterial infection that often occurs during viral infections. The information gained in understanding of how these innate receptors work can inform design of better small molecule adjuvants that target these receptors.
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