Research in the Laboratory of Molecular Immunology is directed at defining the intercellular communication pathways controlling immune responses. Our work is focused on the Tumor Necrosis Factor (TNF)-related cytokines in regulating decisions of cell survival and death, especially in responses to viral pathogens. Translational research is redirecting the communication networks of TNF superfamily to alter the course of autoimmune and infectious disease and cancer.

The laboratory’s work has lead to the discovery of several members of TNF cytokine superfamily and their signaling circuitry. The importance of the signaling circuitry of the immediate family of TNF related cytokines is apparent in the diversity of physiological systems dependent upon their function. TNF, LTαβ and LIGHT modulate lymphoid organ development, homeostasis, and architecture representing cellular interactions between lymphocytes, antigen presenting cells and surrounding stromal cells. These cellular interactions initiate effective host defenses to viral pathogens. Moreover, our studies on modulation the TNF/LT related cytokines by viruses is revealing novel targets for intervention in autoimmune diseases.

The Lymphotoxin-αβ and LIGHT cytokine systems, along with TNF, form an integrated cytokine-signaling circuit that regulates the development and homeostasis of the innate and adaptive immune systems (Fig. 1). The TNF related cytokines assemble as trimers and cluster their specific cell surface receptors to initiate signaling. Both TNF and LTα bind two TNF receptors (TNFR) type 1 and 2. LTα forms a heterotrimer with membrane anchored LTβ creating a ligand with distinct receptor specificity. In contrast with LTα, the LTα1β2 heterotrimer signals exclusively via the LTβ receptor (LTβR), which is expressed on stromal and myeloid cells. LTβR is also activated by another ligand, LIGHT, which binds to the herpesvirus entry mediator (HVEM). A viral ligand, the envelope glycoprotein D of Herpes Simplex virus also binds to HVEM. The signaling pathways activated by these receptors show commonality, yet distinctions exist that reveal each pathway’s unique contribution to cellular differentiation. A goal of the laboratory is to develop a full understanding of the integrated physiological functions of these cytokines in disease pathogenesis. Targeting TNF aids in controlling inflammation in some but not all autoimmune diseases, thus, elucidating the fundamental properties of these communication circuits may provide new opportunities in the clinic.