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 journalArticle

2 Citations (Scopus)

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

Fingerprint

Germinal Center
Receptor Protein-Tyrosine Kinases
Autoimmunity
Ligands
B-Lymphocytes
Immunoglobulin Class Switching
T-Lymphocytes
Immune Tolerance
Protein-Tyrosine Kinases
Dendritic Cells
Necrosis
RNA
Cytokines
DNA

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Cite this

Schell, Stephanie L. ; Soni, Chetna ; Fasnacht, Melinda J. ; Domeier, Phillip P. ; Cooper, Timothy K. ; Rahman, Ziaur S.M. / Mer receptor tyrosine kinase signaling prevents self-ligand sensing and aberrant selection in germinal centers. In: Journal of Immunology. 2017 ; Vol. 199, No. 12. pp. 4001-4015.
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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.",
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Mer receptor tyrosine kinase signaling prevents self-ligand sensing and aberrant selection in germinal centers. / Schell, Stephanie L.; Soni, Chetna; Fasnacht, Melinda J.; Domeier, Phillip P.; Cooper, Timothy K.; Rahman, Ziaur S.M.

In: Journal of Immunology, Vol. 199, No. 12, 15.12.2017, p. 4001-4015.

Research output: Contribution to journalArticle

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AU - Schell, Stephanie L.

AU - Soni, Chetna

AU - Fasnacht, Melinda J.

AU - Domeier, Phillip P.

AU - Cooper, Timothy K.

AU - Rahman, Ziaur S.M.

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