CD4+ T-Cells With High Common γ Chain Expression and Disturbed Cytokine Production Are Enriched in Children With Type-1 Diabetes

Seyfarth, Julia; Mütze, Nathalie; Cruz, Jennifer; Kummer, Sebastian; Reinauer, Christina; Mayatepek, Ertan; Meißner, Thomas; Jacobsen, Marc

doi:10.3389/fimmu.2019.00820

Cited by 9 publications

(11 citation statements)

References 37 publications

(55 reference statements)

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“…Indeed, a previous study suggested that inactivation of FoxO1, a signaling mediator downstream of IGF1R whose activity is inhibited by IGF1 (29), upregulates expression of CD122 in naïve murine CD4 + T cells (64). There is a scarcity of literature on modulation of expression of CD132 levels on T cells (65,66), suggesting that IL-2 + IGF1 may constitute a novel means to sensitize naïve Tconv to cytokines whose receptors utilize the common γ-chain, including but not limited to IL-2 and IL-7 (10). These findings further promote the notion that the influence of IGF1 on the inflammatory/regulatory balance may be highly dependent on the cytokine milieu.…”

Section: Discussionmentioning

confidence: 99%

Insulin-like Growth Factor-1 Synergizes with IL-2 to Induce Homeostatic Proliferation of Regulatory T cells

Shapiro

Peters

Brown

et al. 2022

Preprint

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IL-2 has been proposed to restore tolerance via regulatory T cell (Treg) expansion in autoimmunity, yet off-target effects necessitate identification of a combinatorial approach. We recently reported reduced levels of immunoregulatory insulin-like growth factor-1 (IGF1) during type 1 diabetes (T1D) progression. Thus, we hypothesized that IGF1 would synergize with IL-2 to expand Tregs. We observed IGF1R was elevated on murine memory and human naïve Treg subsets. IL-2 and IGF1 promoted murine PI3K/Akt and human STAT5 signaling in Tregs. IL-2 and IGF1 treatment expanded Tregs beyond either agent alone in NOD mice. Incubation of naïve human CD4+T cells with IL-2 and IGF1 enhanced Treg proliferationin vitro, without the need for T cell receptor ligation. This synergism was attributed to increased high-affinity IL-2Rα expression on naïve Tregs, in contrast to intermediate-affinity IL-2Rβ and IL-2Rγ subunit enhancement on naïve conventional T cells (Tconv). We then demonstrated that IGF1 and IL-2 or the IL2Rγ-chain-dependent cytokine, IL-7, can be used to induce proliferation of genetically-engineered naïve Treg or Tconv cells, respectively. These data support the potential use of IGF1 in combination with common γ-chain cytokines to drive T cell expansions bothin vitroandin vivofor cellular therapeutics and genetic modifications.

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Section: Discussionmentioning

confidence: 99%

Insulin-like Growth Factor-1 Synergizes with IL-2 to Induce Homeostatic Proliferation of Regulatory T cells

Shapiro

Peters

Brown

et al. 2022

Preprint

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“…These cells acquire effector function in the islets, a process dependent on cytokine action (34,35). Common g chain cytokines are important for T-cell proliferation and the generation of self-reactive T cells in autoimmune diseases (9). JAK inhibitors block the catalytic activity of JAKs and they are unlikely to affect cells that are not responding to cytokine stimulation, for example in a non-inflammatory setting (36).…”

Section: Discussionmentioning

confidence: 99%

“…Investigations show that IL-2 and IL-21 are the prime cytokines needed for growth and differentiation of CTL (7,8). IL-7 and IL-15 are responsible for the generation of self-reactive T-cells in autoimmune diseases (9). Treatment with anti-IL-7 receptor-a reverses established autoimmune diabetes in NOD mice (10).…”

Section: Introductionmentioning

confidence: 99%

The JAK1 Selective Inhibitor ABT 317 Blocks Signaling Through Interferon-γ and Common γ Chain Cytokine Receptors to Reverse Autoimmune Diabetes in NOD Mice

Jhala

Fynch

et al. 2020

Front. Immunol.

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Cytokines that signal through the JAK-STAT pathway, such as interferon-γ (IFN-γ) and common γ chain cytokines, contribute to the destruction of insulin-secreting β cells by CD8+ T cells in type 1 diabetes (T1D). We previously showed that JAK1/JAK2 inhibitors reversed autoimmune insulitis in non-obese diabetic (NOD) mice and also blocked IFN-γ mediated MHC class I upregulation on β cells. Blocking interferons on their own does not prevent diabetes in knockout NOD mice, so we tested whether JAK inhibitor action on signaling downstream of common γ chain cytokines, including IL-2, IL-7 IL-15, and IL-21, may also affect the progression of diabetes in NOD mice. Common γ chain cytokines activate JAK1 and JAK3 to regulate T cell proliferation. We used a JAK1-selective inhibitor, ABT 317, to better understand the specific role of JAK1 signaling in autoimmune diabetes. ABT 317 reduced IL-21, IL-2, IL-15 and IL-7 signaling in T cells and IFN-γ signaling in β cells, but ABT 317 did not affect GM-CSF signaling in granulocytes. When given in vivo to NOD mice, ABT 317 reduced CD8+ T cell proliferation as well as the number of KLRG+ effector and CD44hiCD62Llo effector memory CD8+ T cells in spleen. ABT 317 also prevented MHC class I upregulation on β cells. Newly diagnosed diabetes was reversed in 94% NOD mice treated twice daily with ABT 317 while still on treatment at 40 days and 44% remained normoglycemic after a further 60 days from discontinuing the drug. Our results indicate that ABT 317 blocks common γ chain cytokines in lymphocytes and interferons in lymphocytes and β cells and are thus more effective against diabetes pathogenesis than IFN-γ receptor deficiency alone. Our studies suggest use of this class of drug for the treatment of type 1 diabetes.

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“…В модели воспаления in vitro при добавлении IL-7 увеличилась доля CD127 + CD132 + Tem, однако, влияния на экспрессию субъединиц IL-7R Tcm под действием провоспалительных факторов не было выявлено. Интересно, что по данным литературы, обнаруженное у пациентов с сахарным диабетом 1 типа увеличение экспрессии γ-цепи и IL-7Rα на CD4 + клетках памяти воздействовало на передачу сигналов от рецептора и продукцию цитокинов эффекторными Т-клетками [23]. Отсутствие контактов с АПК приводило к снижению содержания CD127 + CD132 + клеток в обеих субпопуляциях Т-клеток памяти, что может говорить о необходимости в дополнительном сигнале при стимуляции IL-7.…”

Section: Discussionunclassified

In vitro maintaining of CD4+ central and effector memory cells in normal and inflammatory conditions

et al. 2020

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IL-7 is a key factor for the survival and maintenance of CD4+ central (Tcm) and effector (Tem) memory cells in the whole body. In many autoimmune diseases, an elevated level of IL-7 is detected in blood serum and at the site of inflammation, thus suggesting participation of this homeostatic factor in the survival of memory T cells, including auto-reactive clones, in inflammatory disorders. The aim of the study was to investigate the mechanisms of maintaining CD4+ memory T cells under normal and inflammatory conditions. We developed an in vitro model of inflammation, based on induction of pro-inflammatory cytokines, and then evaluated the effects of IL-7 upon purified sorted populations of CD4+Tcm and Tem under normal conditions and in vitro inflammatory model. IL-7 treatment promoted maintenance of CD4+Tcm phenotype in all variants of cultures. In the absence of contact with adherent cell fraction, the IL-7-induced proliferation of Tcm and Tem was slightly reduced, both under normal and inflammatory conditions, thus suggesting low sensitivity of memory T cells to contacts with MHC, and, probably, a requirement for additional signals to provide complete stimulation with IL-7. The last suggestion is also supported by data about CD127 and CD132 expression, i.e., in the absence of contact with MHC, the proportion of CD127+CD132+ cells was decreased in both subpopulations of CD4+ memory cells. Upon in vitro cultures, IL-7 contributed to decreased expression of CD127, and increased expression of CD132 on CD4+Tcm and Tem. We have evaluated the CD4+Tcm and Tem populations by affinity of T cell receptor (TCR), using the level of CD5 expression. Т cells with high TCR affinity for self-antigens are known to have higher expression of CD5. In comparison to Tem, the Tcm contained more CD5high cells. In cultures, IL-7 promoted a high level of CD5 expression on Tcm, which was comparable to levels observed in peripheral blood cells. High CD5 expression on Tem was observed after stimulation with IL-7 in the in vitro inflammatory model. In the absence of contact with MHC, the number of CD5high cells decreased among CD4+Tem and Tcm. Thus, CD4+Tcm cells with high affinity for autologous antigens are probably dependent on the presence of homeostatic factors, in particular, IL-7, and contacts with antigen-presenting cells (APCs). Under conditions of inflammation, no changes were revealed in the mechanism of maintaining CD4+Tcm, in contrast to CD4+Tem. Being less dependent on IL-7 under normal conditions, CD4+CD5highTem are accumulated in the presence of IL-7 under in vitro inflammatory conditions.

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CD4+ T-Cells With High Common γ Chain Expression and Disturbed Cytokine Production Are Enriched in Children With Type-1 Diabetes

Cited by 9 publications

References 37 publications

Insulin-like Growth Factor-1 Synergizes with IL-2 to Induce Homeostatic Proliferation of Regulatory T cells

Insulin-like Growth Factor-1 Synergizes with IL-2 to Induce Homeostatic Proliferation of Regulatory T cells

The JAK1 Selective Inhibitor ABT 317 Blocks Signaling Through Interferon-γ and Common γ Chain Cytokine Receptors to Reverse Autoimmune Diabetes in NOD Mice

In vitro maintaining of CD4+ central and effector memory cells in normal and inflammatory conditions

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