Self-Renewing Islet TCF1+ CD8 T Cells Undergo IL-27–Controlled Differentiation to Become TCF1− Terminal Effectors during the Progression of Type 1 Diabetes

Ciecko, Ashley E.; Schauder, David M.; Foda, Bardees M.; Kasmani, Moujtaba Y.; Burns, Robert T.; Lin, Chien‐Wei; Drobyski, William R.; Cui, Weiguo; Chen, Yi-Guang

doi:10.4049/jimmunol.2100362

Cited by 21 publications

(32 citation statements)

References 93 publications

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“…Regulon analysis predicted enriched activity of TCR signaling-induced TFs such as Nfkb1 and Jun ( Courtney et al, 2018 ) in recently activated islet CD8 T cells as would be expected. In addition, recently activated, bystander, and progenitor cells in the islets all had high predicted activity of Stat3, a TF downstream of IL-27 signaling; this is supported by our recent work showing that IL-27 signaling promotes progenitor to effector CD8 T-cell differentiation in the islets of NOD mice ( Ciecko et al, 2021 ). Conversely, islet effector cells exhibited increased activity of TFs associated with aerobic glycolysis, such as Hif1a ( Shi et al, 2011 ) and Foxk2 ( Sukonina et al, 2019 ); aerobic glycolysis is crucial for the effector function of activated T cells ( Gupta et al, 2020 ), and we have found that Hif1a is also up-regulated in effector-like tumor-infiltrating lymphocytes ( Topchyan et al, 2021 ).…”

Section: Resultssupporting

confidence: 58%

“…(A) Colors correspond to the clusters shown in (A). (A, D) Dot plot showing module scores within each cluster from (A) of the top 100 differentially expressed genes in the four CD8 T cell clusters previously identified in non-obese diabetic islets ( Ciecko et al, 2021 ). (D, E) As in (D), but using the top 100 differentially expressed genes among previously identified splenic CD8 T cell clusters from LCMV Clone 13 infection ( Zander et al, 2019 ).…”

Section: Resultsmentioning

confidence: 99%

“…We have previously used scRNA-seq to identify four major subsets of CD8 T cells (bystander, progenitor, effector, and mitotic) in the islets of NOD mice at 7 and 14 wk of age ( Ciecko et al, 2021 ); our previous work, as well as that from other groups ( Hu et al, 2020 ; Gearty et al, 2022 ), has shown that progenitor cells give rise to effector cells that then mediate insulitis. Our current study has much higher resolution as we were able to collect and pool a much greater number of cells for scRNA-seq, allowing us to identify greater heterogeneity in the diabetogenic CD8 T-cell pool compared with our previous work ( Ciecko et al, 2021 ). To compare the cells in our current data with our previously identified subsets, we generated module scores from differentially expressed genes of the four subsets in our previous publication ( Fig 2D ).…”

Section: Resultsmentioning

confidence: 99%

“…Over the last three decades, CD8 T cells have been studied more extensively in the context of chronic or relapsing inflammatory conditions such as chronic viral infections ( Moskophidis et al, 1993 ; Zajac et al, 1998 ; Wherry et al, 2003 ), cancers ( Ahmadzadeh et al, 2009 ; Siddiqui et al, 2019 ), and autoimmune conditions including T1D ( McKinney et al, 2015 ; Long et al, 2016 ; Hu et al, 2020 ). Application of high-throughput sequencing, including single-cell RNA sequencing (scRNA-seq), to models of these various inflammatory states by our laboratory and others has shown previously unappreciated heterogeneity in the CD8 T-cell compartment, demonstrating the coexistence of progenitor-, effector-, and exhausted-like CD8 T cells in these conditions ( He et al, 2016 ; Im et al, 2016 ; Chen et al, 2019 , 2021 ; Hudson et al, 2019 ; Zander et al, 2019 ; Abdelsamed et al, 2020 ; Beltra et al, 2020 ; Sandu et al, 2020 ; Wiedeman et al, 2020 ; Zakharov et al, 2020 ; Ciecko et al, 2021 ; Connolly et al, 2021 ; Gearty et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

“…However, CD8 T-cell clonal heterogeneity in the context of T1D remains understudied at the single-cell level. Given recent advancements in the use of high-throughput sequencing to better define T-cell phenotypes and clonotypes, and to build upon recent work from our laboratory and others demonstrating that islet-specific CD8 T cells are composed of self-renewing progenitor cells that give rise to effector cells ( Ciecko et al, 2021 ; Gearty et al, 2022 ), we decided to investigate the phenotypic and clonal landscapes of CD8 T cells from the islets and spleens of prediabetic NOD mice using paired scRNA-seq and scTCR-seq with a particular focus on CD8 T cells targeting the immunodominant autoantigen IGRP 206-214 .…”

Section: Introductionmentioning

confidence: 99%

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Autoreactive CD8 T cells in NOD mice exhibit phenotypic heterogeneity but restricted TCR gene usage

et al. 2022

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Type 1 diabetes (T1D) is an autoimmune disorder defined by CD8 T cell–mediated destruction of pancreatic β cells. We have previously shown that diabetogenic CD8 T cells in the islets of non-obese diabetic mice are phenotypically heterogeneous, but clonal heterogeneity remains relatively unexplored. Here, we use paired single-cell RNA and T-cell receptor sequencing (scRNA-seq and scTCR-seq) to characterize autoreactive CD8 T cells from the islets and spleens of non-obese diabetic mice. scTCR-seq demonstrates that CD8 T cells targeting the immunodominant β-cell epitope IGRP206-214exhibit restricted TCR gene usage. scRNA-seq identifies six clusters of autoreactive CD8 T cells in the islets and six in the spleen, including memory and exhausted cells. Clonal overlap between IGRP206-214–reactive CD8 T cells in the islets and spleen suggests these cells may circulate between the islets and periphery. Finally, we identify correlations between TCR genes and T-cell clonal expansion and effector fate. Collectively, our work demonstrates that IGRP206-214–specific CD8 T cells are phenotypically heterogeneous but clonally restricted, raising the possibility of selectively targeting these TCR structures for therapeutic benefit.

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