Follicular helper T cell signature in type 1 diabetes

Research output: Contribution to journalArticlepeer-review

Authors

  • Rupert Kenefeck
  • Chun Jing Wang
  • Tauseef Kapadi
  • Lukasz Wardzinski
  • Louise E Clough
  • Frank Heuts
  • Alexandros Kogimtzis
  • Sapna Patel
  • Miranda Rosenthal
  • Masahiro Ono
  • David M Sansom
  • Lucy S K Walker

External organisations

  • University of Birmingham, Birmingham.

Abstract

The strong genetic association between particular HLA alleles and type 1 diabetes (T1D) indicates a key role for CD4+ T cells in disease; however, the differentiation state of the responsible T cells is unclear. T cell differentiation originally was considered a dichotomy between Th1 and Th2 cells, with Th1 cells deemed culpable for autoimmune islet destruction. Now, multiple additional T cell differentiation fates are recognized with distinct roles. Here, we used a transgenic mouse model of diabetes to probe the gene expression profile of islet-specific T cells by microarray and identified a clear follicular helper T (Tfh) cell differentiation signature. Introduction of T cells with a Tfh cell phenotype from diabetic animals efficiently transferred diabetes to recipient animals. Furthermore, memory T cells from patients with T1D expressed elevated levels of Tfh cell markers, including CXCR5, ICOS, PDCD1, BCL6, and IL21. Defects in the IL-2 pathway are associated with T1D, and IL-2 inhibits Tfh cell differentiation in mice. Consistent with these previous observations, we found that IL-2 inhibited human Tfh cell differentiation and identified a relationship between IL-2 sensitivity in T cells from patients with T1D and acquisition of a Tfh cell phenotype. Together, these findings identify a Tfh cell signature in autoimmune diabetes and suggest that this population could be used as a biomarker and potentially targeted for T1D interventions.

Details

Original languageEnglish
Pages (from-to)292-303
Number of pages12
JournalJournal of Clinical Investigation
Volume125
Issue number1
Publication statusPublished - Jan 2015

Keywords

  • Adult, Animals, Autoantigens, Case-Control Studies, Diabetes Mellitus, Type 1, Female, Humans, Immunologic Memory, Interleukin-2, Interleukins, Lymph Nodes, Lymphocyte Activation, Male, Mice, Inbred BALB C, Mice, Transgenic, Pancreas, Receptors, CXCR5, T-Lymphocytes, Helper-Inducer, Transcriptome, Up-Regulation