Lymphotoxin-Dependent B Cell-FRC Crosstalk Promotes De Novo Follicle Formation and Antibody Production following Intestinal Helminth Infection

Abstract

Secondary lymphoid tissues provide specialized niches for the initiation of adaptive immune responses and undergo a remarkable expansion in response to inflammatory stimuli. Although the formation of B cell follicles was previously thought to be restricted to the postnatal period, we observed that the draining mesenteric lymph nodes (mLN) of helminth-infected mice form an extensive number of new, centrally located, B cell follicles in response to IL-4Rα-dependent inflammation. IL-4Rα signaling promoted LTα1β2 (lymphotoxin) expression by B cells, which then interacted with CCL19 positive stromal cells to promote lymphoid enlargement and the formation of germinal center containing B cell follicles. Importantly, de novo follicle formation functioned to promote both total and parasite-specific antibody production. These data reveal a role for type 2 inflammation in promoting stromal cell remodeling and de novo follicle formation by promoting B cell-stromal cell crosstalk.

Repetitive ischemic injuries to the kidneys result in lymph node fibrosis and impaired healing

“…Next, we tested the hypothesis that T cells can activate FRCs through the action of membrane-bound lymphotoxin α (LTα), as FRCs express LTβr (37)(38)(39), the receptor to which LTα binds. We performed the adoptive transfer of T cells (2. Figure 3A).…”

Potential of Cells and Cytokines/Chemokines to Regulate Tertiary Lymphoid Structures in Human Diseases

“…A fully structured TLS depends on LTβ expression by B cells (34). After exposure to continuous stimuli in a chronic inflammatory environment, B cells upregulate lymphotoxin expression through IL-4Rα signaling and promote FRC proliferation and activation via lymphotoxin-LTβR signaling (35). Moreover, B cells contribute to local immune responses to persisting autoantigens by producing proinflammatory cytokines, chemokines and growth factors, all of which are crucial for TLS formation.…”

IL-4/CXCL12 loop is a key regulator of lymphoid stroma function in follicular lymphoma

“…22 Interestingly, mouse B cells respond to the IL-4 burst associated with intestinal helminth infection by an increase in their expression of LT, which then interacts with LTbR 1 FRCs to induce their expansion and reorganization. 48 However, such a process is unlikely to take place in FL, given the downregulation of LT on malignant B cells. In agreement, we revealed that primary FL B cells were not able to stimulate in vitro CXCL12 production in stromal cells, whereas FL-T FH cells were efficient CXCL12 inducers.…”