Differentiation of follicular helper T cells by salivary gland epithelial cells in primary Sjögren's syndrome

J Autoimmun. 2014 Jun;51:57-66. doi: 10.1016/j.jaut.2013.11.003. Epub 2014 Jan 9.

Abstract

Follicular helper T cells (Tfh), which play a pivotal role in B cell activation and differentiation in lymphoid structures, secrete IL-21 whose augmented secretion is a hallmark of several autoimmune diseases. To decipher the cellular and molecular interactions occurring in salivary glands of patients suffering from primary Sjögren's syndrome (pSS), we investigated whether salivary gland epithelial cells (SGECs) were capable to induce Tfh differentiation. Co-cultures of naïve CD4(+) T cells and SGECs from both patients with pSS and controls were performed. Here, we report that IL-6 and ICOSL expression by SGECs contributes to naïve CD4(+) T differentiation into Tfh cells, as evidenced by their acquisition of a specific phenotype, characterized by Bcl-6, ICOS and CXCR5 expression and IL-21 secretion, but also but by their main functional feature: the capacity to enhance B lymphocytes survival. We demonstrated an increase of serum IL-21 with systemic activity. Finally, we analyzed the potential occurrence of a genetic association between IL-21 or IL-21R gene polymorphisms and pSS or elevated IL-21 secretion. This study, which demonstrates a direct induction of Tfh differentiation by SGECs, emphasizes a yet unknown pathogenic role of SGECs and suggests that Tfh and IL-21 might be relevant biomarkers and/or therapeutic targets in primary Sjögren's syndrome.

Keywords: Epithelial cells; Follicular helper T cells; Germinal centers; IL-21; Sjögren's syndrome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism
  • Case-Control Studies
  • Cell Communication / immunology
  • Cell Differentiation*
  • Cell Survival / immunology
  • Cells, Cultured
  • Coculture Techniques
  • Epithelial Cells / metabolism*
  • Germinal Center / immunology
  • Germinal Center / metabolism
  • Humans
  • Immunophenotyping
  • Inducible T-Cell Co-Stimulator Ligand / metabolism
  • Interleukin-6 / blood
  • Interleukin-6 / metabolism
  • Interleukins / blood
  • Interleukins / genetics
  • Interleukins / metabolism
  • Lymphocyte Activation / immunology
  • Polymorphism, Single Nucleotide
  • Receptors, Interleukin-21 / genetics
  • Salivary Glands / immunology*
  • Salivary Glands / metabolism*
  • Salivary Glands / pathology
  • Severity of Illness Index
  • Sjogren's Syndrome / immunology*
  • Sjogren's Syndrome / metabolism*
  • Sjogren's Syndrome / pathology
  • T-Lymphocytes, Helper-Inducer / cytology*
  • T-Lymphocytes, Helper-Inducer / immunology*

Substances

  • ICOSLG protein, human
  • Inducible T-Cell Co-Stimulator Ligand
  • Interleukin-6
  • Interleukins
  • Receptors, Interleukin-21
  • interleukin-21