IL-1–induced Bhlhe40 identifies pathogenic T helper cells in a model of autoimmune neuroinflammation

Lin, Chih‐Chung; Bradstreet, Tara R.; Schwarzkopf, Elizabeth A.; Jarjour, Nicholas N.; Chou, Chun; Archambault, Angela S.; Sim, Julia; Zinselmeyer, Bernd H.; Carrero, Javier A.; Wu, Gregory F.; Taneja, Reshma; Artyomov, Maxim N.; Russell, John H.; Edelson, Brian T.

doi:10.1084/jem.20150568

Cited by 78 publications

(125 citation statements)

References 67 publications

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“…These authors also found that transmigration through the blood-spinal cord barrier triggered pro-IL-1β expression by neutrophils, and that at day seven after EAE induction, IL-1β-producing neutrophils were found in the blood. We and others also found IL-1β-producing myeloid cells in peripheral lymphoid organs at days five through eight following EAE induction (31, 32, 36, 62). These reports collectively identified a population of CD11b + Ly6C mid-hi MHC II lo-hi monocyte-derived DC/macrophages (moDCs/Macs) as the main source of IL-1β in draining lymph nodes (DLNs), and showed that these cells increase dramatically following MOG 35-55 /CFA immunization given with PTX coadjuvant.…”

Section: Cellular Sources Of Il-1β In Eaesupporting

confidence: 73%

New Insights into the Role of IL-1β in Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis

Lin

Edelson

2017

The Journal of Immunology

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118

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Multiple sclerosis, and its animal model experimental autoimmune encephalomyelitis, are neuroinflammatory diseases driven by autoreactive pathogenic TH cells which elicit demyelination and axonal damage. How TH cells acquire pathogenicity and communicate with myeloid cells and cells of the central nervous system remain unclear. IL-1β is recognized to play an important role in EAE and perhaps MS. Clinical EAE is significantly attenuated in IL-1 receptor-deficient and IL-1β-deficient mice, and IL-1β is found in the blood, cerebrospinal fluid, and CNS lesions of MS patients. Here, we will focus on new reports which elucidate the cellular sources of IL-1β and its actions during EAE, in both lymphoid tissues and within the CNS. Several immune cell types serve as critical producers of IL-1β during EAE, with the cytokine inducing responses in hematopoietic and non-hematopoietic cells. These findings from the EAE model should inspire efforts towards investigating the therapeutic potential of IL-1 blockade in MS.

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Section: Cellular Sources Of Il-1β In Eaesupporting

confidence: 73%

New Insights into the Role of IL-1β in Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis

Lin

Edelson

2017

The Journal of Immunology

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118

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“…Further, we detected a number of transcription factors that were differentially expressed in Csf1 + compared to Csf1 - T cells (S2 Table); it may be that one or more of these acts in concert with TBET to exert a distinct transcriptional program in Csf1 + cells. Indeed, one of the differentially expressed transcription factors in our dataset, Bhlhe40 , was recently shown to drive GM-CSF expression in a fraction of Th1 and Th17 cells during experimental autoimmune encephalitis [79–81]. Previous studies on the gene expression profiles of CD4 + T cells polarized in vitro detected Csf1 transcript in Th2 cells [82], and found no defect in Csf1 expression in Bhlhe40 -deficient CD4 + T cells [80]; however, given that we detected little Csf1 expression in cells polarized in vitro relative to those isolated from infected mice, we hypothesize that these previous gene expression studies lack a robust positive control for Csf1 expression, and instead are measuring relatively low levels of transcript that may not be physiologically meaningful.…”

Section: Discussionmentioning

confidence: 99%

Macrophage Colony Stimulating Factor Derived from CD4+ T Cells Contributes to Control of a Blood-Borne Infection

et al. 2016

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Dynamic regulation of leukocyte population size and activation state is crucial for an effective immune response. In malaria, Plasmodium parasites elicit robust host expansion of macrophages and monocytes, but the underlying mechanisms remain unclear. Here we show that myeloid expansion during P. chabaudi infection is dependent upon both CD4+ T cells and the cytokine Macrophage Colony Stimulating Factor (MCSF). Single-cell RNA-Seq analysis on antigen-experienced T cells revealed robust expression of Csf1, the gene encoding MCSF, in a sub-population of CD4+ T cells with distinct transcriptional and surface phenotypes. Selective deletion of Csf1 in CD4+ cells during P. chabaudi infection diminished proliferation and activation of certain myeloid subsets, most notably lymph node-resident CD169+ macrophages, and resulted in increased parasite burden and impaired recovery of infected mice. Depletion of CD169+ macrophages during infection also led to increased parasitemia and significant host mortality, confirming a previously unappreciated role for these cells in control of P. chabaudi. This work establishes the CD4+ T cell as a physiologically relevant source of MCSF in vivo; probes the complexity of the CD4+ T cell response during type 1 infection; and delineates a novel mechanism by which T helper cells regulate myeloid cells to limit growth of a blood-borne intracellular pathogen.

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“…The IL-1R1 signaling pathway has received a renewed attention due to its recently reported induction of transcription factor Bhlhe40 associated with Th17 cell encephalitogenic phenotype and GM-CSF secretion (38). Furthermore, the role of IL-1 signaling in the generation of autoimmune responses was most recently documented by the production of IL-1 by neutrophils and monocytes as they migrate to the CNS and induce IL-1R signaling in endothelial cells, which trigger the release of proinflammatory cytokines and chemokines that enhance neutrophil and monocyte recruitment and further T cell recruitment to the CNS (39).…”

Section: Discussionmentioning

confidence: 99%

Activated IL-1RI Signaling Pathway Induces Th17 Cell Differentiation via Interferon Regulatory Factor 4 Signaling in Patients with Relapsing-Remitting Multiple Sclerosis

Sha

Marković-Pleše

2016

Front. Immunol.

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IL-1β plays a crucial role in the differentiation of human Th17 cells. We report here that IL-1RI expression is significantly increased in both naive and memory CD4+ T cells derived from relapsing-remitting multiple sclerosis (RR MS) patients in comparison to healthy controls. Interleukin 1 receptor (IL-1R)I expression is upregulated in the in vitro-differentiated Th17 cells from RR MS patients in comparison to the Th1 and Th2 cell subsets, indicating the role of IL-1R signaling in the Th17 cell differentiation in RR MS. When IL-1RI gene expression was silenced using siRNA, human naive CD4+ T cells cultured in the presence of Th17-polarizing cytokines had a significantly decreased expression of interleukin regulatory factor 4 (IRF4), RORc, IL-17A, IL-17F, IL-21, IL-22, and IL-23R genes, confirming that IL-1RI signaling induces Th17 cell differentiation. Since IL-1R gene expression silencing inhibited IRF4 expression and Th17 differentiation, and IRF4 gene expression silencing inhibited Th17 cell differentiation, our results indicate that IL-1RI induces human Th17 cell differentiation in an IRF4-dependant manner. Our study has identified that IL-1RI-mediated signaling pathway is constitutively activated, leading to an increased Th17 cell differentiation in IRF4-dependent manner in patients with RR MS.

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IL-1–induced Bhlhe40 identifies pathogenic T helper cells in a model of autoimmune neuroinflammation

Abstract: Lin et al. show that Bhlhe40 expression identifies encephalitogenic CD4+ T helper cells and define a pertussis toxin–IL-1–Bhlhe40 pathway active in experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis.

Cited by 78 publications

References 67 publications

New Insights into the Role of IL-1β in Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis

New Insights into the Role of IL-1β in Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis

Macrophage Colony Stimulating Factor Derived from CD4+ T Cells Contributes to Control of a Blood-Borne Infection

Activated IL-1RI Signaling Pathway Induces Th17 Cell Differentiation via Interferon Regulatory Factor 4 Signaling in Patients with Relapsing-Remitting Multiple Sclerosis

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