Redefining the Role of Lymphotoxin Beta Receptor in the Maintenance of Lymphoid Organs and Immune Cell Homeostasis in Adulthood

Abstract

Lymphotoxin beta receptor (LTβR) is a promising therapeutic target in autoimmune and infectious diseases as well as cancer. Mice with genetic inactivation of LTβR display multiple defects in development and organization of lymphoid organs, mucosal immune responses, IgA production and an autoimmune phenotype. As these defects are imprinted in embryogenesis and neonate stages, the impact of LTβR signaling in adulthood remains unclear. Here, to overcome developmental defects, we generated mice with inducible ubiquitous genetic inactivation of LTβR in adult mice (iLTβRΔ/Δ mice) and redefined the role of LTβR signaling in organization of lymphoid organs, immune response to mucosal bacterial pathogen, IgA production and autoimmunity. In spleen, postnatal LTβR signaling is required for development of B cell follicles, follicular dendritic cells (FDCs), recruitment of neutrophils and maintenance of the marginal zone. Lymph nodes of iLTβRΔ/Δ mice were reduced in size, lacked FDCs, and had disorganized subcapsular sinus macrophages. Peyer`s patches were smaller in size and numbers, and displayed reduced FDCs. The number of isolated lymphoid follicles in small intestine and colon were also reduced. In contrast to LTβR-/- mice, iLTβRΔ/Δ mice displayed normal thymus structure and did not develop signs of systemic inflammation and autoimmunity. Further, our results suggest that LTβR signaling in adulthood is required for homeostasis of neutrophils, NK, and iNKT cells, but is dispensable for the maintenance of polyclonal IgA production. However, iLTβRΔ/Δ mice exhibited an increased sensitivity to C. rodentium infection and failed to develop pathogen-specific IgA responses. Collectively, our study uncovers new insights of LTβR signaling in adulthood for the maintenance of lymphoid organs, neutrophils, NK and iNKT cells, and IgA production in response to mucosal bacterial pathogen.

Mature B cells and mesenchymal stem cells control emergency myelopoiesis

“…LTβR and TNFR signaling blockade also reduced the rate of myeloid progenitor proliferation in vivo, whereas BrdU incorporation in common lymphoid progenitors and in megakaryocyte/erythroid progenitors (MEPs) was unaffected in vivo ( Fig S1G ). In line with the reported role of IL-1R in supporting inflammation-induced emergency myelopoiesis ( Ueda et al, 2009 ) and LTβR signaling in the homeostasis of neutrophils in the spleen ( Shou et al, 2021 ), blocking of IL-1R in addition to LTβR and TNFR led to a further reduction in inflammatory monocytes and neutrophil numbers in the spleen ( Fig S1F ).…”

Age-Associated Changes to Lymph Node Fibroblastic Reticular Cells

“…However, expression of LT ligands remained abundant in aged hematopoietic cells. The role of LTβ signaling in early lymph node stromal development is well-appreciated ( Bénézech et al, 2010 ; Brendolan and Caamaño 2012 ), and its importance in postnatal stromal maintenance has been recently been highlighted ( Chai et al, 2013 ; Li et al, 2019 ; Shou et al, 2021 ). However, unlike models of genetically abrogated Ltbr , we find a more subtle decrease in stromal Ltbr expression with age, and changes to LTBR expression were more plainly revealed once FRCs were subsetted based on their upregulation of VCAM-1.…”

“…Committed progenitors, known as lymphoid tissue organizer (LTo) cells, differentiate into FRCs in a lymphotoxin-beta (LTβ)-dependent manner ( Bénézech et al, 2010 ). Inducible deletion of Ltbr in adult mice resulted in loss of lymph nodes and Peyer’s patches ( Shou et al, 2021 ), indicating that receptor activity remains important in the postnatal period. LTβ signals appear to be important for enforcing the immunoregulatory function of FRCs in the postnatal lymph node, as FRC-specific ablation of lymphotoxin-beta receptor (LTβR) resulted in poor pathogen clearance ( Chai et al, 2013 ).…”

Induction of toxicity in human colon cells and organoids by size- and composition-dependent road dust

“…Chemokine (C-X-C motif) ligand (CXCL)1, CXCL2, CXCL3 and CXCL8 are strong neutrophil chemoattractants and are associated with immune responses. 41,42 Lipocalin-2 (LCN2) is expressed in neutrophils, and binding to NGAL is important in immune responses 43 Lymphotoxin beta (LTB) is an inducer of the inammatory response 44,45 , and an increased level of serum amyloid A1 (SAA1) is associated with inammatory amyloidosis. 46,47 Increased levels of these genes are all related to an increase in the immune response.…”