TNF-α Limits Serological Memory by Disrupting the Bone Marrow Niche

Tonya Aaron, Ethan Laudermilch, Zachary Benet, Luis Jose Ovando, Kartik Chandran, David Fooksman

Research output: Contribution to journalArticlepeer-review

Abstract

Both infection and autoimmune disease can disrupt pre-existing Ab titers leading to diminished serological memory, yet the underlying mechanisms are not well understood. In this article, we report that TNF-α, an inflammatory cytokine, is a master regulator of the plasma cell (PC) niche in the bone marrow (BM). Acute rTNF-α treatment depletes previously existing Ab titers after vaccination by limiting PC occupancy or retention in the BM. Consistent with this phenomenon, mice lacking TNF-α signaling have elevated PC capacity in the BM and higher Ab titers. Using BM chimeric mice, we found that PC egress from the BM is regulated in a cell-extrinsic manner, by radiation-resistant cells via TNF-α receptor 1 signaling, leading to increased vascular permeability and CD138 downregulation on PCs. PC motility and egress in the BM are triggered within 6 h of recombinant TNF-α treatment. In addition to promoting egress, TNF-α signaling also prevented re-engraftment into the BM, leading to reduced PC survival. Although other inflammatory stimuli can promote PC egress, TNF-α signaling is necessary for limiting the PC capacity in the BM. Collectively, these data characterize how TNF-α-mediated inflammation attenuates the durability of serological memory and shapes the overall size and composition of the Ab-secreting cell pool in the BM.

Original languageEnglish (US)
Pages (from-to)595-608
Number of pages14
JournalJournal of Immunology
Volume210
Issue number5
DOIs
StatePublished - Mar 1 2023

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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