Details

Autor(en) / Beteiligte

• Ciecko, Ashley E
• Schauder, David M
• Foda, Bardees M
• Lin, Chien-Wei
• Cui, Weiguo
• Chen, Yi-Guang

Titel

Single-cell transcriptome analysis reveals diverse islet-infiltrating T cell subsets and a role for BATF in promoting the diabetogenic activity of CD8 T cells

Ist Teil von

• The Journal of immunology (1950), 2019-05, Vol.202 (1_Supplement), p.115-115.20

Erscheinungsjahr

2019

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• Abstract T cells infiltrate pancreatic islets and directly mediate the destruction of insulin-producing β cells during the development of type 1 diabetes (T1D). However, islet-infiltrating T cell differentiation states and functional diversity have not been completely defined. We used unbiased single-cell RNA sequencing analyses to define the phenotypic complexity of islet-infiltrating T cells in non-obese diabetic (NOD) mice. In the CD4 T cell compartment, we identified naïve, memory, and regulatory T cells, as well as multiple Il21 expressing effector subsets positive for markers indicative of Th1 and Tfh cells. In the CD8 T cell compartment, we identified naïve cells and two activated subsets defined by Slamf6 or Cxcr6 expression, respectively resembling the self-renewing progenitor cells and terminally differentiated effectors found during chronic lymphocytic choriomeningitis virus (LCMV) infection. Single-cell regulatory network inference and clustering (SCENIC) analysis revealed that regulon activity of several transcription factors with known roles in effector CD8 T cell function including Batf were turned on in the Slamf6+ and Cxcr6+ cells. Previous studies have shown that IL-21 induced BATF expression in CD8 T cells is critical to sustain their effector function against chronic LCMV infection. Similarly, we found lower BATF expression in activated islet CD8 T cells from NOD. Il21+/− compared to NOD mice. We further demonstrated that overexpression of BATF in β cell autoreactive CD8 T cells eliminated their need for IL-21 to cause T1D. Our results reveal phenotypically diverse and novel islet-infiltrating T cell subsets and suggest a model in which the IL-21-BATF pathway is critical for the diabetogenic activity of CD8 T cells.