Effector CD4 T cells with progenitor potential mediate chronic intestinal inflammation

Shin, Boyoung; Kress, Robert; Kramer, Philip; Darley‐Usmar, Victor; Bellis, Susan L.; Harrington, Laurie E.

doi:10.1084/jem.20172335

Cited by 26 publications

(22 citation statements)

References 45 publications

(67 reference statements)

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“…However, the sialidase used in these prior studies cleaves both α2–3 and α2–6 sialic acids, which may not be biologically equivalent to selective changes in α2–6 sialylation induced by alterations in ST6Gal-I expression. Fluctuations in ST6Gal-I levels are biologically relevant, in that ST6Gal-I expression is dynamically regulated in certain immune cell populations [ 3 , 39 , 40 ], and typically upregulated in epithelial malignancies [ 41 , 42 ]. Moreover, another group utilized a sialidase specific for α2–3 sialic acids, along with lectins that block either α2–3 or α2–6 sialic acids, and determined that it was the α2–3, but not α2–6, sialic acids that hindered TLR4 receptor activation and signaling [ 43 ].…”

Section: Discussionmentioning

confidence: 99%

“…In other studies, a highly pathogenic subset of stem-like CD4 T cells was identified in a mouse model of colitis. Significantly, these T cells have enriched ST6Gal-I and are also resistant to apoptosis [ 39 ]. Many of these aforementioned studies indicate that ST6Gal-I is vital for immune cell differentiation and/or activation, suggesting that ST6Gal-I regulates immune cell fate.…”

Section: Discussionmentioning

confidence: 99%

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Regulation of inflammatory signaling by the ST6Gal-I sialyltransferase

et al. 2020

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The ST6Gal-I sialyltransferase, an enzyme that adds α2-6-linked sialic acids to N-glycosylated proteins, regulates multiple immunological processes. However, the contribution of receptor sialylation to inflammatory signaling has been under-investigated. In the current study, we uncovered a role for ST6Gal-I in promoting sustained signaling through two prominent inflammatory pathways, NFκB and JAK/STAT. Using the U937 monocytic cell model, we determined that knockdown (KD) of ST6Gal-I expression had no effect on the rapid activation of NFκB by TNF (≤ 30 min), whereas long-term TNF-induced NFκB activation (2–6 hr) was diminished in ST6Gal-I-KD cells. These data align with prior work in epithelial cells showing that α2–6 sialylation of TNFR1 prolongs TNF-dependent NFκB activation. Similar to TNF, long-term, but not short-term, LPS-induced activation of NFκB was suppressed by ST6Gal-I KD. ST6Gal-I KD cells also exhibited reduced long-term IRF3 and STAT3 activation by LPS. Given that ST6Gal-I activity modulated LPS-dependent signaling, we conducted pull-down assays using SNA (a lectin specific for α2–6 sialic acids) to show that the LPS receptor, TLR4, is a substrate for sialylation by ST6Gal-I. We next assessed signaling by IFNγ, IL-6 and GM-CSF, and found that ST6Gal-I-KD had a limited effect on STAT activation induced by these cytokines. To corroborate these findings, signaling was monitored in bone marrow derived macrophages (BMDMs) from mice with myeloid-specific deletion of ST6Gal-I (LysMCre/ST6Gal-Ifl/fl). In agreement with data from U937 cells, BMDMs with ST6Gal-I knockout displayed reduced long-term activation of NFκB by both TNF and LPS, and diminished long-term LPS-dependent STAT3 activation. However, STAT activation induced by IFNγ, IL-6 and GM-CSF was comparable in wild-type and ST6Gal-I knockout BMDMs. These results implicate ST6Gal-I-mediated receptor sialylation in prolonging the activity of select signaling cascades including TNF/NFκB, LPS/NFκB, and LPS/STAT3, providing new insights into ST6Gal-I’s role in modulating the inflammatory phenotype of monocytic cells.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Regulation of inflammatory signaling by the ST6Gal-I sialyltransferase

et al. 2020

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“…[138][139][140] Long-lived T H 17 cells with stem cell-like attributes of self-renewal and multipotency were also found. 141 Interest in stem-like T helper cells has recently increased by reports of their involvement in autoimmune diseases, including chronic colitis 142 and experimental autoimmune encephalomyelitis. 132 The functional identification of these cells has revealed another dimension in T helper cell differentiation that is only decipherable under specific disease contexts but is physiologically relevant.…”

Section: T-cell Plasticity and Heterogeneitymentioning

confidence: 99%

Helper T cell differentiation

2019

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CD4 + T helper cells are key regulators of host health and disease. In the original model, specialized subsets of T helper cells are generated following activation through lineage-specifying cytokines and transcriptional programs, but recent studies have revealed increasing complexities for CD4 + T-cell differentiation. Here, we first discuss CD4 + T-cell differentiation from a historical perspective by highlighting the major studies that defined the distinct subsets of T helper cells. We next describe the mechanisms underlying CD4 + T-cell differentiation, including cytokine-induced signaling and transcriptional networks. We then review current and emerging topics of differentiation, including the plasticity and heterogeneity of T cells, the tissue-specific effects, and the influence of cellular metabolism on cell fate decisions. Importantly, recent advances in cutting-edge approaches, especially systems biology tools, have contributed to new concepts and mechanisms underlying T-cell differentiation and will likely continue to advance this important research area of adaptive immunity.

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“…CD4 + T cells mainly contain effector CD4 + T cells such as T helper 1 (Th1), Th2, Th17, and regulatory T cells (Tregs). Studies have shown that intestinal immune homeostasis depends on the regulation and balance of these CD4 + T cell subgroups, and the deregulated overexpansion and activation of Th1 and Th17 cells in relation to Tregs can lead to intestinal inflammation, such as IBD [10–12]. Since Th1 and Th17 cells could secrete large amounts of proinflammatory cytokines such as IFN- γ , TNF- α , IL-1 β , and IL-17, resulting in persistent intestinal inflammation [13], medications that can suppress colonic oxidative status and inhibit Th1/Th17 responses would be shown to be clinically effective.…”

Section: Introductionmentioning

confidence: 99%

Indigo Naturalis Suppresses Colonic Oxidative Stress and Th1/Th17 Responses of DSS-Induced Colitis in Mice

Xiao

Jiao

Wen

et al. 2019

Oxidative Medicine and Cellular Longevity

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Indigo naturalis (also known as Qing-dai, or QD), a traditional Chinese medicine, has been widely used as an anticolitis regimen in the clinical practice of Chinese medicine. However, the precise mechanisms behind its efficacy remain unknown. We investigated the protective effects and associated molecular mechanisms of QD in DSS-induced colitis in mice. We found that QD administration attenuated DSS-induced colon shortening, tissue damage, and the disease activity index during the onset of colitis. Moreover, QD administration significantly suppressed colonic MPO activity and increased the activities of colonic T-SOD, CAT, and GSH-Px, as well the expression of p-AMPK and Nrf-2 in colon tissues of colitic mice. In addition, QD was capable of reducing the colonic Th1 and Th17 cell cytokines, the frequencies of Th1 and Th17 cells, and the phosphorylation of p-STAT1 and p-STAT3 in the mesenteric lymph nodes of colitic mice. An in vitro assay showed that QD significantly suppressed the differentiation of Th1 and Th17 cells. These findings suggest that QD has the potential to alleviate experimental colitis by suppressing colonic oxidative stress and restraining colonic Th1/Th17 responses, which are associated with activating AMPK/Nrf-2 signals and inhibiting STAT1/STAT3 signals, respectively. These findings also support QD as an effective regimen in the treatment of IBD.

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Effector CD4 T cells with progenitor potential mediate chronic intestinal inflammation

Cited by 26 publications

References 45 publications

Regulation of inflammatory signaling by the ST6Gal-I sialyltransferase

Regulation of inflammatory signaling by the ST6Gal-I sialyltransferase

Helper T cell differentiation

Indigo Naturalis Suppresses Colonic Oxidative Stress and Th1/Th17 Responses of DSS-Induced Colitis in Mice

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