Research

We are interested in the molecular mechanisms which underlie the processes of lymphocyte activation and tolerance. Our particular areas of current focus are in lymphocyte signaling and interactions between innate and adaptive immune receptors.

The following is a summary of key projects ongoing in the lab :

  1. How does TRAF3 regulate B lymphocyte survival and activation?  How does TRAF3 act as a tumor suppressor in B cell cancers?  How does loss of TRAF3 in aging and chronic inflammation contribute to autoimmunity and predispose to malignancy?

    Members of the tumor necrosis factor receptor (TNFR) superfamily participate in many events that regulate cell activation and programmed cell death. Most signals induced by receptors of this family are delivered via cytoplasmic (CY) adapter molecules belonging to the TNFR-associated factor (TRAF) family. The family member TRAF3 can play diverse, even sharply contrasting roles in signaling by different receptors, and in different cell types. Although whole-mouse deficiency in TRAF3 is lethal, we produced a conditional TRAF3-deficient mouse strain that permits us to assess the functions of TRAF3 in distinct cell types. Mice lacking TRAF3 specifically in B cells show dramatically increased B cell survival, with normal cell proliferation. This results in massively enlarged secondary lymphoid organs, autoimmune manifestations by young adulthood, and development of B cell tumors as mice age. Interestingly, although TRAF3 deficiency results in constitutive activation of the ‘noncanonical’ or “NF-kB2” signaling pathway in all cell types examined to date, TRAF3 deficiency leads to markedly enhanced survival ONLY in B cells. We are investigating the molecular mechanisms by which TRAF3 deficiency regulates cell survival uniquely in B lymphocytes. We recently also found that TRAF3 associates with the B cell antigen receptor complex (BCR), and inhibits BCR signaling; we are investigating the molecular mechanism(s) for this regulation. This information could permit greater efficacy in designing treatments for B cell malignancies, as it can inform the targeting of non-proliferating cells that could survive standard chemotherapy.

  2. What roles does TRAF3 play in regulation of signaling and effector functions of T lymphocytes?

    We also produced mice that lack TRAF3 specifically in T cells.  Unlike B cells, TRAF3-deficient T cells have no alterations in survival.  Instead, these T cells show marked decreases in CD4+ and CD8+ T cell function in response to infection and immunization.  Additionally, invariant NK T cell development and function are severely compromised in these mice, in a manner attributable to the reduced TCR signaling and upregulation of the transcription factor T-bet.  In the absence of TRAF3, signaling through the TCR is compromised from the earliest measurable event, the activation of Src kinases.  We also found that TRAF3 associates with the TCR complex.   Key to this process appears to be blocking by TRAF3 of association with the TCR of the Src kinase inhibitor Csk.  Our recent work shows that TRAF3 associates with the TCR via interaction with the TCR adapter LAT, and restrains several negative regulators of the LAT molecule, to ultimately enhance TCR signaling. TRAF3 also regulates signaling through the IL-2 receptor by association with Jak molecules and the T cell phosphatase TCPTP.  This regulation restrains IL-2 responses of thymic T regulatory cell precursors, and in the absence of T cell TRAF3, mice have an increased number of nTreg cells with elevated IL-2 responses.  Recent investigations are probing how T cell TRAF3 enhances signaling by the type 1 interferon receptor, and in contrast limits signaling by the TNRF family costimulator GITR.

  3. How does CD40 signaling contribute to early resistance of cells to infection with Ebola and SARS-CoV-2 viruses?

    Our lab has studied the critical costimulatory molecule CD40 for several decades.  Recent collaborative studies with our virologist colleague Dr. Wendy Maury are building upon findings that CD40-deficient mice show increased susceptibility to early infection by Ebola and SARS-CoV-2, to determine the mechanism by which CD40 can act as an early, ‘innate’ protective signal to host cells, as well as its well-known roles in adaptive immunity.