An autoimmune stem-like CD8 T cell population drives type 1 diabetes

Gearty, Sofia V; Dündar, Friederike; Zumbo, Paul; Espinosa-Carrasco, Gabriel; Shakiba, Mojdeh; Sánchez‐Rivera, Francisco J.; Socci, Nicholas D.; Trivedi, Prerak; Lowe, Scott W.; Lauer, Peter; Mohibullah, Neeman; Viale, Agnès; DiLorenzo, Teresa P.; Betel, Doron; Schietinger, Andrea

doi:10.1038/s41586-021-04248-x

Cited by 118 publications

(120 citation statements)

References 57 publications

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“…This observation suggests that CD4 + CD25 + CD226 - Tregs may not only be longer-lived, but potentially, localize more readily in secondary lymphoid organs ( 17 ). This remains a critical issue for Treg-ACT applications in the context of T1D, as Tregs must be able to migrate to sites of inflammation and priming, specifically to the pancreatic draining lymph nodes where recent studies have revealed the presence of a stem-cell like CD8 + T cell progenitor population that significantly contributes to pancreatic β-cell destruction in the NOD model of T1D ( 67 ).…”

Section: Discussionmentioning

confidence: 99%

Human CD4+CD25+CD226- Tregs Demonstrate Increased Purity, Lineage Stability, and Suppressive Capacity Versus CD4+CD25+CD127lo/- Tregs for Adoptive Cell Therapy

et al. 2022

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Regulatory T cell (Treg) adoptive cell therapy (ACT) represents an emerging strategy for restoring immune tolerance in autoimmune diseases. Tregs are commonly purified using a CD4+CD25+CD127lo/- gating strategy, which yields a mixed population: 1) cells expressing the transcription factors, FOXP3 and Helios, that canonically define lineage stable thymic Tregs and 2) unstable FOXP3+Helios- Tregs. Our prior work identified the autoimmune disease risk-associated locus and costimulatory molecule, CD226, as being highly expressed not only on effector T cells but also, interferon-γ (IFN-γ) producing peripheral Tregs (pTreg). Thus, we sought to determine whether isolating Tregs with a CD4+CD25+CD226- strategy yields a population with increased purity and suppressive capacity relative to CD4+CD25+CD127lo/- cells. After 14d of culture, expanded CD4+CD25+CD226- cells displayed a decreased proportion of pTregs relative to CD4+CD25+CD127lo/- cells, as measured by FOXP3+Helios- expression and the epigenetic signature at the FOXP3 Treg-specific demethylated region (TSDR). Furthermore, CD226- Tregs exhibited decreased production of the effector cytokines, IFN-γ, TNF, and IL-17A, along with increased expression of the immunoregulatory cytokine, TGF-β1. Lastly, CD226- Tregs demonstrated increased in vitro suppressive capacity as compared to their CD127lo/- counterparts. These data suggest that the exclusion of CD226-expressing cells during Treg sorting yields a population with increased purity, lineage stability, and suppressive capabilities, which may benefit Treg ACT for the treatment of autoimmune diseases.

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Section: Discussionmentioning

confidence: 99%

Human CD4+CD25+CD226- Tregs Demonstrate Increased Purity, Lineage Stability, and Suppressive Capacity Versus CD4+CD25+CD127lo/- Tregs for Adoptive Cell Therapy

et al. 2022

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“…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 ).…”

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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“…In contrast to multi-potential effector conventional T cells and their “stem-like” source cells, terminally differentiated effector T cells are often characterized as exhausted or dysfunctional: contributing minimally to clearing infectious agents, controlling tumor progression, or causing autoimmune disease (Gearty et al, 2021; Im et al, 2016; Siddiqui et al, 2019; Utzschneider et al, 2016). However, support for this characterization largely comes from studies of CD8 + T cells, and it remains unclear whether this concept extends to Treg cells.…”

Section: Resultsmentioning

confidence: 99%

Terminal differentiation and persistence of effector regulatory T cells essential for the prevention of intestinal inflammation

Dikiy

Levine

Pritykin

et al. 2022

Preprint

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SUMMARYRegulatory T (Treg) cells represent a specialized CD4+ T cell lineage with essential anti-inflammatory functions. Recent studies of Treg cell adaptation to non-lymphoid tissue environments to carry out specialized immunosuppressive and tissue supportive functions raises questions about the mechanisms underlying these different adaptions and whether they represent stable differentiation or reversible activation states. Using novel genetic tools, we characterized the transcriptional programs of distinct colonic effector Treg cell types. We show that attenuated T cell receptor (TCR) signaling and acquisition of substantial TCR independent functionality appears to facilitate the terminal differentiation of a population of colonic effector Treg cells distinguished by stable expression of immunomodulatory cytokine Interleukin (IL)-10. We show that this subset of colonic effector Treg cells, but not their expression of IL-10, was indispensable for preventing colitis. Our results suggest core features of terminal differentiation of effector Treg cells in non-lymphoid tissues and their function therein. (148 words)

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An autoimmune stem-like CD8 T cell population drives type 1 diabetes

Cited by 118 publications

References 57 publications

Human CD4+CD25+CD226- Tregs Demonstrate Increased Purity, Lineage Stability, and Suppressive Capacity Versus CD4+CD25+CD127lo/- Tregs for Adoptive Cell Therapy

Human CD4+CD25+CD226- Tregs Demonstrate Increased Purity, Lineage Stability, and Suppressive Capacity Versus CD4+CD25+CD127lo/- Tregs for Adoptive Cell Therapy

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

Terminal differentiation and persistence of effector regulatory T cells essential for the prevention of intestinal inflammation

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