Signal Transduction in Immune Responses and Lymphoid Malignancies

The primary research interest of our laboratory is the molecular mechanisms regulating normal immune responses to viruses and bacteria and lymphoid malignancies, such as T-cell leukemia and lymphoma.

Project #1. T-cell activation and HTLV-induced T-cell leukemia

This project investigates the signal transduction pathways and downstream transcription factors mediating normal T-cell activation and human T-cell leukemia virus (HTLV)-induced T-cell transformation. Antigen-induced T cell activation serves as a critical step in the development of an imB and NF-AT in T-Cell Activation and Retroviral Pathogenesis">mune response. This step is tightly controlled by a genetic program involving transduction of signals from cell surface receptors to the nucleus, triggering transcription of various genes involved in cell growth, survival, and differentiation. Under normal situations, the T-cell signaling events occur transiently, and the activated T cells eventually cease growth and die of apoptosis or become memory cells. Deregulated T-cell activation and proliferation may lead to immunological disorders, such as autoimmune diseases, or even the development of T-cell malignancies. One example of the latter is seen with T-cell infection by HTLV. HTLV induces constitutive expression of various growth-regulatory cellular genes, resulting in abnormal proliferation and subsequent transformation of host cells, which lead to the development of a fatal T-cell malignancy, termed adult T-cell leukemia (ATL). A major focus of our research is the signal transduction pathway leading to activation of NF-kB, a key transcription factor mediating both normal T-cell activation and HTLV-induced T-cell transformation.

Project #2. Molecular mechanisms regulating inflammatory responses and septic shock

Inflammatory response is an important mechanism of host defense against bacterial infections. However, exaggerated systemic responses, due to overwhelming infections, may cause septic shock, which is associated with a large number of human fatalities. In Gram-negative infection, the endotoxin LPS is largely responsible for inducing inflammation and septic shock. This bacterial cell wall component stimulates the production of various inflammatory mediators by macrophages through triggering the Toll-like receptor 4 (TLR4) signaling pathway. However, the signaling steps connecting TLR4 to the downstream biochemical events remain poorly defined. This knowledge is important for rational design of strategies to modulate immune responses against bacterial infections and to treat inflammation and endotoxic shock.

Our laboratory has recently shown that stimulation of macrophages with LPS leads to rapid activation of a serine/threonine protein kinase, termed Tpl2 (also named Cot). This upstream kinase was originally identified as a protooncogene product, whose aberrant expression and structural alterations are associated with both human and animal cancers. At least in transfected cells, Tpl2 induces the activity of a number of downstream kinases, including the MAP kinases (MAPKs) and IkB kinases (IKK), leading to activation of multiple transcription factors. Gene knockout studies reveal an essential role for Tpl2 in regulation of macrophage responses to bacteria and as well as the induction of septic shock in mice. One part of our studies in this area is to investigate the molecular melchanisms by which Tpl2 is activated upon LPS stimulation and to identify downstream genes regulated by this signaling pathway. We are also trying to understand how Tpl2 is oncogenically activated in tumor cells. Both human cell culture and animal (mouse) models are being used in our studies.