Neonatal Basophils Stifle the Function of Early-Life Dendritic Cells To Curtail Th1 Immunity in Newborn Mice

Self Cite

Early thymic progenitors (ETPs) are endowed with diverse potencies and can give rise to myeloid and lymphoid lineage progenitors. How the thymic environment guides ETP commitment and maturation towards a specific lineage remains obscure. We have previously shown that ETPs expressing the heteroreceptor (HR) comprising IL-4 receptor alpha (IL-4Rα) and IL-13 receptor alpha 1 (IL-13Rα1) give rise to myeloid but not T cells. Here we show that signaling through the HR inhibits ETP maturation to the T cell lineage but enacts commitment towards the myeloid cells. Indeed, HR-positive ETPs (HR+ETPs), but not HR-negative ETPs (HR−ETPs), exhibit activated STAT6 transcription factor which parallels with downregulation of Notch1, a critical factor for T cell development. Meanwhile, myeloid-specific transcription factor, C/EBPα, usually under the control of Notch1 is up-regulated. Furthermore, in vivo inhibition of STAT6 phosphorylation restores Notch1 expression in HR+ETPs which regain T-lineage potential. In addition, upon stimulation with IL-4 or IL-13 HR−ETPs expressing virally transduced HR, also exhibit STAT 6 phosphorylation and down-regulation of Notch1 leading to inhibition of lymphoid but not myeloid lineage potential. These observations indicate that environmental cytokines play a role in conditioning ETP lineage choice which would impact T cell development.

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

IL-4/IL-13 Signaling Inhibits the Potential of Early Thymic Progenitors To Commit to the T Cell Lineage

Barik

Miller

Cattin-Roy

et al. 2017

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“…This study however shows that Th1 and Th17 cells display different pattern of sensitivity to Treg suppression in both 13R +/+ and 13R -/- mice. Since Th1 and Th17 cells do not express the HR even in 13R +/+ mice, it is likely that the sensitivity to Treg suppression is guided by APCs whose function had been shaped by the HR (15, 16, 20, 21). It is possible that the interaction of naïve T cells with HR-conditioned APCs not only guides subset differentiation but also prompts expression of surface molecules that control the sensitivity of the effector to Treg suppression (41-44).…”

Section: Discussionmentioning

confidence: 99%

“…Also IL-4 does not signal through the conventional IL-4R (IL-4Rα/common γ chain) in Th1 cells (17) and the conventional IL-13 receptor (IL-13Rα1/IL-13Rα2) serves rather as a decoy receptor (18). Thus, mice lacking IL-13Rα1 in which the conventional IL-4R is intact but the HR does not form (19-21) provide a suitable model to determine whether anti-inflammatory IL-4/IL-13 synergize with Tregs to maintain peripheral tolerance and contain EAE. This was indeed the case as IL-13Rα1-deficient (13R -/- ) mice which lack the HR (HR -/- ) are more susceptible to EAE relative to 13R +/+ wild type mice.…”

Section: Introductionmentioning

confidence: 99%

IL-4/IL-13 Heteroreceptor Influences Th17 Cell Conversion and Sensitivity to Regulatory T Cell Suppression To Restrain Experimental Allergic Encephalomyelitis

Barik

Ellis

Cascio

et al. 2017

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IL-4 and IL-13 have been defined as anti-inflammatory cytokines which can counter myelin-reactive T cells and modulate experimental allergic encephalomyelitis (EAE). However, it is not known whether endogenous IL-4 and IL-13 contribute to the maintenance of peripheral tolerance and whether their function is coordinated with T regulatory cells (Tregs). Here, we utilized mice in which the common cytokine receptor for IL-4 and IL-13, namely the IL-4Rα/IL-13Rα1 heteroreceptor (HR), is compromised and determined whether the lack of signaling by endogenous IL-4 and IL-13 through the HR influences the function of effector Th1 and Th17 cells in a Treg-dependent fashion. The findings indicate that mice-deficient for the HR (13R-/-) are more susceptible to EAE than mice sufficient for the HR (13R+/+) and develop early onset and more severe disease. Moreover, Th17 cells from 13R-/- mice had reduced ability to convert to Th1 cells and displayed reduced sensitivity to suppression by Tregs relative to Th17 effectors from 13R+/+ mice. These observations suggest that IL-4 and IL-13 likely operate through the HR and influence Th17 cells to convert to Th1 cells and to acquire increased sensitivity to suppression leading to control of immune-mediated central nervous system inflammation. These previously unrecognized findings shed light on the intricacies underlying the contribution of cytokines to peripheral tolerance and control of autoimmunity.

“…It has long been known that type II cytokines, such as IL-4 and IL-13, function as anti-inflammatory in mouse and human T1D (3–6). For instance, neonatal Th1 cells unusually upregulate the IL-4Rα/IL-13Rα1 heteroreceptor (HR) (7) and both IL-4 and IL-13 signal death of these inflammatory cells (8). However, adult Th1 cells do not express the IL-4Rα/IL-13Rα1 heteroreceptor (HR) and the conventional IL-4 receptor (IL-4R), comprising IL-4Rα and the common gamma chain (IL-4R/γ), does not signal in these cells (9).…”

Section: Introductionmentioning

confidence: 99%

On the Role IL-4/IL-13 Heteroreceptor Plays in Regulation of Type 1 Diabetes

Ukah

Cattin-Roy

Chen

et al. 2017

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Type 1 diabetes (T1D) manifests when the insulin-producing pancreatic beta-cells are destroyed as a consequence of an inflammatory process initiated by lymphocytes of the immune system. The non-obese diabetic (NOD) mouse develops T1D spontaneously and serves as an animal model for human T1D. The heteroreceptor (HR), comprising IL-4Rα and IL-13Rα1, serves both IL-4 and IL-13 cytokines which are believed to function as anti-inflammatory cytokines in T1D. However, whether the HR provides a responsive element to environmental (i.e. physiologic) IL-4/IL-13 in the regulation of peripheral tolerance and the development of T1D has yet to be defined. In this study, NOD mice deficient for the HR have been generated by means of IL-13Rα1 gene disruption and used to determine whether such deficiency affects the development of T1D. Surprisingly, the findings indicate that NOD mice lacking the HR (13R−/−) display resistance to T1D as the rise in blood glucose level (BGL) and islet inflammation were significantly delayed in these HR-deficient relative to HR-sufficient (13R+/+ ) mice. In fact, the frequency and spleen- to-pancreas dynamics of both Th1 and Th17 cells were affected in 13R−/− mice. This is likely due to an increase in the frequency of mTGFβ+FoxP3int Tregs and persistence of CD206+ macrophages in the pancreas as both types of cells confer resistance to T1D upon transfer to 13R+/+ mice. These findings reveal new insights as to the role environmental IL-4/IL-13 and the HR play in peripheral tolerance and the development of T1D.