Lymphoid Tissue Stromal Cells Regulate Lymph Node and Peyer's Patch Homeostasis and Facilitate Adaptive Immune Responses

Abstract

The initiation of adaptive immune responses depends upon the careful maneuvering of lymphocytes and antigen into and within strategically placed lymphoid tissues. Non-hematopoietic stromal cells form the cellular infrastructure that directs this process. Once regarded as merely structural features of lymphoid tissues, these cells are now appreciated as essential regulators of immune cell trafficking, fluid flow, and lymph node homeostasis. Recent advances in the identification and in vivo targeting of specific stromal populations have revealed important insights into the population heterogeneity and functional complexity of lymphoid tissue stromal cells. Here, we attempt to expand on these findings by describing a novel model of CXCL13-cre-directed cellular ablation. These studies have allowed us to characterize the specific contributions of the CXCL13-expressing stromal cell compartment to lymphoid tissue homeostasis. We have additionally sought to provide new insights to the functions of stromal cells in intestinal Peyer's patches – an area which, until recently, has been largely overlooked. Peyer's patches (PPs) are B cell-rich lymphoid tissues situated throughout the small intestine which play an important role in mucosal antibody responses. PP architecture and stromal cell composition closely resemble that of peripheral lymph nodes despite geographical and functional differences. Notably, fibroblastic stromal cells located in small intestinal PPs form a network of collagen-rich reticular fibers similar to the network of conduits found in lymph nodes. Unlike lymph nodes, PPs lack a conventional source of afferent lymph that would normally contribute fluid flow through the conduit network. Instead fluid flow through PP conduits depends largely on water absorbed across the intestinal epithelium. We find that by disrupting water absorption, we can limit or prevent the contribution of absorbed lumenal fluids to the flow of PP conduits. Disruption of fluid absorption subsequently has profound effects on the structural integrity of the high endothelial venules and surrounding perivascular FRCs and correlates with a striking defect in the recruitment of naïve recirculating lymphocytes to the PP. Prolonged disruption additionally impacts mucosal antibody responses. We believe these findings reveal a critical role for conduit-mediated fluid flow in the maintenance of Peyer's patch homeostasis and mucosal immune function.