Mer receptor tyrosine kinase signaling prevents self-ligand sensing and aberrant selection in germinal centers

Stephanie L. Schell, Chetna Soni, Melinda J. Fasnacht, Phillip P. Domeier, Timothy K. Cooper, Ziaur S.M. Rahman

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Mer tyrosine kinase (Mer) signaling maintains immune tolerance by clearing apoptotic cells (ACs) and inducing immunoregulatory signals. We previously showed that Mer-deficient mice (Mer-/-) have increased germinal center (GC) responses, T cell activation, and AC accumulation within GCs. Accumulated ACs in GCs can undergo necrosis and release self-ligands, which may influence the outcome of a GC response and selection. In this study, we generated Mer-/- mice with a global MyD88, TLR7, or TLR9 deficiency and cell type-specific MyD88 deficiency to study the functional correlation between Mer and TLRs in the development of GC responses and autoimmunity. We found that GC B cell-intrinsic sensing of self-RNA, but not self-DNA, released from dead cells accumulated in GCs drives enhanced GC responses in Mer-/- mice. Although self-ligands directly affect GC B cell responses, the loss of Mer in dendritic cells promotes enhanced T cell activation and proinflammatory cytokine production. To study the impact of Mer deficiency on the development of autoimmunity, we generated autoimmune-prone B6. Sle1b mice deficient in Mer (Sle1b.Mer-/-). We observed accelerated autoimmunity development even under conditions where Sle1b.Mer-/- mice did not exhibit increased AC accumulation in GCs compared with B6.Sle1b mice, indicating that Mer immunoregulatory signaling in APCs regulates B cell selection and autoimmunity. We further found significant expansion, retention, and class-switching of autoreactive B cells in GCs under conditions where ACs accumulated in GCs of Sle1b.Mer-/- mice. Altogether, both the phagocytic and immunomodulatory functions of Mer regulate GC responses to prevent the development of autoimmunity.

Original languageEnglish (US)
Pages (from-to)4001-4015
Number of pages15
JournalJournal of Immunology
Volume199
Issue number12
DOIs
StatePublished - Dec 15 2017

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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