title: Follicular helper T cell signature in type 1 diabetes.
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.
authors.forename: Rupert
authors.initials: R
authors.lastname: Kenefeck
authors.forename: Chun Jing
authors.initials: CJ
authors.lastname: Wang
authors.forename: Tauseef
authors.initials: T
authors.lastname: Kapadi
authors.forename: Lukasz
authors.initials: L
authors.lastname: Wardzinski
authors.forename: Kesley
authors.initials: K
authors.lastname: Attridge
authors.forename: Louise E
authors.initials: LE
authors.lastname: Clough
authors.forename: Frank
authors.initials: F
authors.lastname: Heuts
authors.forename: Alexandros
authors.initials: A
authors.lastname: Kogimtzis
authors.forename: Sapna
authors.initials: S
authors.lastname: Patel
authors.forename: Miranda
authors.initials: M
authors.lastname: Rosenthal
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ono
authors.forename: David M
authors.initials: DM
authors.lastname: Sansom
authors.forename: Parth
authors.initials: P
authors.lastname: Narendran
authors.forename: Lucy S K
authors.initials: LS
authors.lastname: Walker
mesh_terms: D000328:Adult; D000818:Animals; D001324:Autoantigens / Q000378:metabolism; D016022:Case-Control Studies; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D005260:Female; D006801:Humans; D007156:Immunologic Memory; D007376:Interleukin-2 / Q000502:physiology; D007378:Interleukins / Q000378:metabolism; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation; D008297:Male; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D010179:Pancreas / Q000276:immunology; D054380:Receptors, CXCR5 / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D059467:Transcriptome; D015854:Up-Regulation / Q000276:immunology; D000098546:Interleukin-21
chemical_list: D001324:Autoantigens; C095085:CXCR5 protein, human; D007376:Interleukin-2; D007378:Interleukins; D054380:Receptors, CXCR5; D000098546:Interleukin-21