Vascular-stromal function and regulation in immunity

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Summary Lymphocytes within lymphoid tissues are regulated by a vascular-stromal compartment comprised of blood vessels, lymphatic sinuses, and non-vascular mesenchymal reticular cells, and understanding the functions and regulation of this compartment can have implications for better understanding and treating lymphoproliferative and autoimmune diseases. We have recently shown that fibroblastic reticular cells (FRCs) are in distinct functional states at homeostasis and in inflamed lymph nodes. Our long-term goal is to understand other functional features of the vascular-stromal compartment in inflamed nodes, how these features contribute to regulating immune responses, and how these features in inflamed nodes are induced. Here, we show that FRCs upregulate CCL2 during a phase of the immune response that corresponds to plasma cell accumulation. FRCs express CCL2 at high levels in the vascular-rich medulla and vascular-rich regions of the T zone, which are also the sites of plasma cell localization. We show that CCL2 limits plasma cell survival and that vascular permeability may play a role in inducing the FRC functional phenotype in these vascular-rich regions. We propose to test the hypothesis that, during this phase of the immune response, features of vascular-rich microenvironments regulate plasma cell function and vascular activity regulates FRC functional phenotype in these areas. Our aims are 1) to understand how CCL2 regulates plasma cell survival and 2) to understand how vascular activity contributes to modulating FRC functional phenotype. The results from this proposal will provide new insights into lymphoid tissue vascular-stromal function and regulation, plasma cell regulation, and a potential link between cardiovascular health and the immune system. This link is especially relevant for autoimmune diseases such as lupus that are characterized both by vascular dysfunction and immune system dysfunction marked in part by plasma cell accumulation