A Subset of Interleukin-21+ Chemokine Receptor CCR9+ T Helper Cells Target Accessory Organs of the Digestive System in Autoimmunity

McGuire, Helen M.; Vogelzang, Alexis; Cindy, S.; Hughes, William E.; Silveira, Pablo A.; Tangye, Stuart G.; Christ, Daniel; Fulcher, David A.; Falcone, Marika; King, Charles M.

doi:10.1016/j.immuni.2011.01.021

Cited by 105 publications

(138 citation statements)

References 60 publications

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“…Recent studies indicate that IL-21R-deficient mice fail to clear chronic viral infections (21)(22)(23) and that IL-21R NOD mice are protected from T1D (24)(25)(26)(27)(28), most likely via impaired CD8 + CTL function (26,29,44). Our data suggest that this generalized impairment of CTL function in the absence of IL-21 signaling may result from impaired induction of T-bet and reduced expression of T-bet-dependent transcriptional programs that promote CTL function.…”

Section: Discussionmentioning

confidence: 60%

“…IL-21 promotes CD8 + T cell responses in the context of tumor immunity and is required for the clearance of chronic viral infections in animal models, suggesting that IL-21 plays a critical role in the regulation of effector CTL responses (20)(21)(22)(23). IL-21 is also required for development of T1D, as IL-21R-deficient mice crossed onto the NOD background are almost completely resistant to the development of T1D; conversely, transgenic mice overexpressing IL-21 in pancreatic islets develop spontaneous diabetes on a resistant genetic background (24)(25)(26)(27)(28)(29). To date, the molecular mechanisms by which IL-21 promotes the development of CD8 + CTL responses have remained unclear.…”

Section: D8mentioning

confidence: 99%

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IL-21 Promotes CD8+ CTL Activity via the Transcription Factor T-bet

Sutherland

Joller

Michaud

et al. 2013

The Journal of Immunology

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CD8+ T cells are fundamental for immune-mediated clearance of viral infections and contribute to immune pathology in autoimmune diseases such as type 1 diabetes. To execute these functions, CD8+ T cells must differentiate into CTLs, a process that is precisely regulated by a variety of cytokines, costimulatory molecules, and transcription factors. IL-21 is an IL-2 family cytokine and a growth factor for multiple lymphocyte effector lineages, including cytotoxic CD8+ T cells. Recent studies demonstrate that loss of IL-21 signaling results in reduced viral clearance in models of lymphocytic choriomeningitis virus infection, and also protection from type 1 diabetes in the NOD model. This is most likely the result of impaired CD8+ CTL function in the absence of IL-21 signaling. Currently, the mechanisms by which IL-21 promotes CTL differentiation in CD8+ T cells remain unclear, particularly the identity of the relevant transcription factor(s). We show that IL-21 promotes CTL function in vitro and killing of pancreatic islets in vivo via the use of transgenic mice expressing IL-21 in pancreatic β cells. We demonstrate that IL-21 induces the expression of the transcription factor T-bet in CD8+ T cells, predominantly via STAT1, and that T-bet is required for the induction of cytolytic molecules, including perforin and granzyme B in response to IL-21. Finally, we show that IL-21–induced CTL function is T-bet dependent, as T-bet deficiency results in defective IL-21–dependent cytotoxicity in CD8+ T cells in vitro and in vivo. Thus, IL-21 drives CD8+ CTL differentiation via the actions of the transcription factor T-bet.

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Section: Discussionmentioning

confidence: 60%

Section: D8mentioning

confidence: 99%

IL-21 Promotes CD8+ CTL Activity via the Transcription Factor T-bet

Sutherland

Joller

Michaud

et al. 2013

The Journal of Immunology

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“…IL-21 + T cells did not coexpress IL-17, suggesting that they were not Th17 cells, but there was substantial coexpression of TNF-α and IFN-γ ( Figure 3, C and D). It has been shown that IL-21 can derive from CCR9 + T cells in NOD mice and patients with Sjögren's syndrome (27); however, pancreas-infiltrating CD4 + T cells showed elevated levels of mRNA for Cxcr5, Pdcd1, and Icos but not Ccr9 (Supplemental Figure 3). To directly test the capacity of T cells with a Tfh cell phenotype to transfer diabetes, DO11 T cells from pooled PanLNs of DO11 RIP-mOVA mice were CXCR5 enriched or depleted by cell sorting and their capacity to transfer diabetes into RIP-mOVA-expressing recipients was assessed.…”

Section: Islet-specific T Cells In the Pancreatic Ln Show A Tfh Gene mentioning

confidence: 99%

Follicular helper T cell signature in type 1 diabetes

Kenefeck¹,

Wang²,

Kapadi³

et al. 2014

J. Clin. Invest.

137

152

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by negative magnetic separation (EasySep Human Naive CD4 + T cell Enrichment Kit, Stem Cell Technologies). Cells were plated at a density of 100,000 per well in a 96-well round bottom plate and stimulated with anti-CD3/28 beads (Human T-Activator Dynabeads, Life Technologies) for 5 days. Where indicated, cultures were treated with 10 ng/ml IL-12 and/or 20 ng/ml IL-2 (both from Peprotech). Statistics. Data were analyzed using Prism statistical software. Statistical significance was assessed using the Mann-Whitney test. Paired data were analyzed using a 2-tailed paired Student's t test. A P value of less than 0.05 was considered significant.

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“…3). In this respect, McGuire et al [84] found that when diabetes was induced in NOD/SCID mice by adoptive transfer of CD4 and CD8 T cells, it was the CD8 T cells that required IL-21R in order for diabetes to develop. Loss of IL-21 sensitivity in the CD4 compartment led to only a partial reduction in diabetes incidence.…”

Section: Possible Roles For Il-21 In Autoimmune Diabetesmentioning

confidence: 99%

CD4 T cell differentiation in type 1 diabetes

Walker

Herrath

2015

Clinical and Experimental Immunology

145

101

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SummarySusceptibility to type 1 diabetes is associated strongly with human leucocyte antigen (HLA) genes, implicating T cells in disease pathogenesis. In humans, CD8 T cells predominantly infiltrate the islets, yet their activation and propagation probably requires CD4 T cell help. CD4 T cells can select from several differentiation fates following activation, and this choice has profound consequences for their subsequent cytokine production and migratory potential. In turn, these features dictate which other immune cell types T cells interact with and influence, thereby determining downstream effector functions. Obtaining an accurate picture of the type of CD4 T cell differentiation associated with a particular immune-mediated disease therefore constitutes an important clue when planning intervention strategies. Early models of T cell differentiation focused on the dichotomy between T helper type 1 (Th1) and Th2 responses, with type 1 diabetes (T1D) being viewed mainly as a Th1-mediated pathology. However, several additional fate choices have emerged in recent years, including Th17 cells and follicular helper T cells. Here we revisit the issue of T cell differentiation in autoimmune diabetes, highlighting new evidence from both mouse models and patient samples. We assess the strengths and the weaknesses of the Th1 paradigm, review the data on interleukin (IL)-17 production in type 1 diabetes and discuss emerging evidence for the roles of IL-21 and follicular helper T cells in this disease setting. A better understanding of the phenotype of CD4 T cells in T1D will undoubtedly inform biomarker development, improve patient stratification and potentially reveal new targets for therapeutic intervention.

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A Subset of Interleukin-21+ Chemokine Receptor CCR9+ T Helper Cells Target Accessory Organs of the Digestive System in Autoimmunity

Cited by 105 publications

References 60 publications

IL-21 Promotes CD8+ CTL Activity via the Transcription Factor T-bet

IL-21 Promotes CD8+ CTL Activity via the Transcription Factor T-bet

Follicular helper T cell signature in type 1 diabetes

CD4 T cell differentiation in type 1 diabetes

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