Deciphering Cytokine Regulation of Lymphocyte Trafficking

About This Grant

The mammalian body is continuously monitored by migratory lymphocytes that traffic via the blood to secondary lymphoid organs (SLO) in search of cognate antigens. In lymph nodes (LN) and Peyer's patches (PP), this critical surveillance mechanism depends on high endothelial venules (HEV), specialized microvessels that support multi-step adhesion cascades for circulating lymphocytes to egress into the extravascular space. HEV are found in all SLO except the spleen. In addition, HEV can arise in sites of chronic inflammation and solid tumors. These ectopic HEV mediate lymphocyte accumulation within tertiary lymphoid tissues (TLO) that may exacerbate pathologic inflammation, but also enhance tumor susceptibility to immunotherapy. Thus, pharmacologic interventions to manipulate HEV could potentially enable new drugs for cancer immunotherapy and inflammatory diseases. HEV formation in LN and PP requires the sustained action of cytokines on venular endothelial cells (EC), particularly lymphotoxin β (LTb). However, EC exposure to LTb alone is insufficient for effective HEV reprogramming, suggesting that other signals are needed. Preliminary work for this project showed a profound loss of HEV in LN and PP of mice in which EC were deficient in CD130 (gp130, IL6ST), the shared signaling subunit of a group of receptors for IL-6 family cytokines. A similar, albeit milder, phenotype was seen when EC lacked LIFR or OSMR, CD130 co-receptors that recognize lymphoma inhibitory factor (LIF) or oncostatin M (OSM), respectively. This project will explore the hypothesis that HEV formation and maintenance depends upon VEC signaling via CD130 upon ligation of LIFR and (to a lesser degree) OSMR. To test this hypothesis, Aim 1 will explore the role of endothelial CD130 in the formation and maintenance of HEV. The frequency, morphology and function of HEV in conditional 'knockout' mouse strains will be examined in steady-state SLO and in models of cancer, inflammatory bowel disease and rheumatoid arthritis. This aim will generate a comprehensive picture of the physiologic and immunological impact of intrinsic CD130 signaling in normal and pathologic HEV. Aim 2 will characterize the cytokine ligand(s) and co- receptor(s) that drive CD130 dependent HEV differentiation. Expression and localization of the known cytokines and co-receptors will be characterized in LN and PP, and HEV phenotype, function and immunological impact will be tested in conditional knockout mice lacking endothelial LIFR or OSMR. This aim will clarify the relative contribution of CD130 agonists and the LTb pathway in LN HEV formation and investigate the role of peripherally produced lymph-borne CD130 ligands vs. cytokines produced within the LN proper. Given the clinical importance of HEV formation and function for human health, this work is highly significant. If successful, the proposed studies may identify novel targets to either promote or inhibit HEV formation to treat human diseases such as cancer or chronic inflammation, respectively.