The transcriptional repressor HIC1 regulates intestinal immune homeostasis

Burrows, Kyle; Antignano, Frann; Bramhall, Michael; Chenery, Alistair; Scheer, Sebastian; Kor̆ínek, Vladimír; Underhill, T. Michael; Zaph, Colby

doi:10.1038/mi.2017.17

Cited by 31 publications

(29 citation statements)

References 63 publications

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“…Hematopoietic cell-specific deletion of HIC1 resulted in ~50% reduction in the number of CD45 + cells in the intestinal lamina propria (LP) ( Fig 1A and 1B ). Consistent with our previous study [ 26 ], we found reduced frequencies and numbers of γδ and αβ T cells in the LP of Hic1 Vav mice ( Fig 1C and 1D ). Further, analysis of macrophage and DC populations in the LP of Hic1 fl/fl and Hic1 Vav mice revealed a specific requirement for HIC1 in CD103 + CD11b + DCs ( Fig 1E and 1F ), which is consistent with previous studies identifying a role for atRA in the regulation of this DC subset [ 12 , 13 ].…”

Section: Resultssupporting

confidence: 93%

“…atRA has been shown to control hematopoietic stem cell dormancy, a profound state of quiescence, that is counteracted by activation of Myc-dependent proliferation [ 39 , 40 ]. As we have previously observed in intestinal T cells, HIC1 is dispensable for the expression of intestinal homing markers and migration to the intestine [ 26 ]. Thus, our current working hypothesis is that RA induces expression of HIC1 to promote cellular quiescence/dormancy in the intestinal microenvironment, possibly by regulating Myc-dependent processes including metabolism and proliferation.…”

Section: Discussionmentioning

confidence: 82%

“…We have previously shown that HIC1 is expressed in a wide variety of immune cells in the intestinal microenvironment, and that deletion of HIC1 specifically in T cells resulted in a severe reduction in the frequency and number of CD4 + and CD8 + T cells in the intestine [ 26 ]. To test if HIC1 played a general role in intestinal immune cell homeostasis, we generated mice with a hematopoietic cell-specific deletion of Hic1 ( Hic1 Vav mice) by crossing mice with loxP sites flanking the Hic1 gene ( Hic1 fl/fl mice) with mice that express the Cre recombinase under control of the Vav promoter ( Vav -Cre mice).…”

Section: Resultsmentioning

confidence: 99%

“…Our results suggest that HIC1 expression in ILC3s is critically important for immunity to intestinal bacterial infection. Using mice with a fluorescent reporter gene inserted in the Hic1 locus ( Hic1 Citrine mice) [ 33 ] we determined that in addition to previously identified populations including T cells, dendritic cells and macrophages [ 26 ], lineage-negative (lin neg ) CD90.2 + CD127 + ILCs isolated from the intestinal LP express HIC1 ( Fig 6A ), which was dependent on the availability of atRA, as Hic1 Citrine mice reared on a VAD diet did not express HIC1 in ILCs within the LP ( Fig 6B ). Loss of HIC1 in RORγt + cells (in Hic1 Rorc mice) resulted in a specific change in ILC populations in the LP.…”

Section: Resultsmentioning

confidence: 99%

“…Importantly, several members of the POK/ZBTB family are key regulators in immune cell differentiation and function, including: BCL6, PLZF and ThPOK [ 21 – 25 ]. Recently, we identified HIC1 as an atRA responsive gene in intestinal T H cells and demonstrated a T cell-intrinsic role for HIC1 in the regulation of intestinal homeostasis as well as in development of several models of intestinal inflammation [ 26 ].…”

Section: Introductionmentioning

confidence: 99%

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HIC1 links retinoic acid signalling to group 3 innate lymphoid cell-dependent regulation of intestinal immunity and homeostasis

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Section: Resultssupporting

confidence: 93%

Section: Discussionmentioning

confidence: 82%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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HIC1 links retinoic acid signalling to group 3 innate lymphoid cell-dependent regulation of intestinal immunity and homeostasis

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Immunomodulatory Microparticles Epigenetically Modulate T Cells and Systemically Ameliorate Autoimmune Arthritis

et al. 2023

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Disease modifying antirheumatic drugs (DMARDs) have improved the prognosis of autoimmune inflammatory arthritides but a large fraction of patients display partial or nonresponsiveness to front-line DMARDs. Here, an immunoregulatory approach based on sustained joint-localized release of all-trans retinoic acid (ATRA), which modulates local immune activation and enhances disease-protective T cells and leads to systemic disease control is reported. ATRA imprints a unique chromatin landscape in T cells, which is associated with an enhancement in the differentiation of naïve T cells into anti-inflammatory regulatory T cells (T reg ) and suppression of T reg destabilization. Sustained release poly-(lactic-co-glycolic) acid (PLGA)-based biodegradable microparticles encapsulating ATRA (PLGA-ATRA MP) are retained in arthritic mouse joints after intra-articular (IA) injection. IA PLGA-ATRA MP enhance migratory T reg which in turn reduce inflammation and modify disease in injected and uninjected joints, a phenotype that is also reproduced by IA injection of T reg . PLGA-ATRA MP reduce proteoglycan loss and bone erosions in the SKG and collagen-induced arthritis mouse models of autoimmune arthritis. Strikingly, systemic disease modulation by PLGA-ATRA MP is not associated with generalized immune suppression. PLGA-ATRA MP have the potential to be developed as a disease modifying agent for autoimmune arthritis.

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Intestinal tissue‐resident memory T cells maintain distinct identity from circulating memory T cells after in vitro restimulation

Beumer‐Chuwonpad,

Behr,

van Alphen

et al. 2024

Eur J Immunol

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Resident memory T (TRM) cells have been recently established as an important subset of memory T cells that provide early and essential protection against reinfection in the absence of circulating memory T cells. Recent findings showing that TRM expand in vivo after repeated antigenic stimulation indicate that these memory T cells are not terminally differentiated. This suggests an opportunity for in vitro TRM expansion to apply in an immunotherapy setting. However, it has also been shown that TRM may not maintain their identity and form circulating memory T cells after in vivo restimulation. Therefore, we set out to determine how TRM respond to antigenic activation in culture. Using Listeria monocytogenes and LCMV infection models, we found that TRM from the intraepithelial compartment of the small intestine expand in vitro after antigenic stimulation and subsequent resting in homeostatic cytokines. A large fraction of the expanded TRM retained their phenotype, including the expression of key TRM markers CD69 and CD103 (ITGAE). The optimal culture of TRM required low O2 pressure to maintain the expression of these and other TRM‐associated molecules. Expanded TRM retained their effector capacity to produce cytokines after restimulation, but did not acquire a highly glycolytic profile indicative of effector T cells. The proteomic analysis confirmed TRM profile retention, including expression of TRM‐related transcription factors, tissue retention factors, adhesion molecules, and enzymes involved in fatty acid metabolism. Collectively, our data indicate that limiting oxygen conditions supports in vitro expansion of TRM cells that maintain their TRM phenotype, at least in part, suggesting an opportunity for therapeutic strategies that require in vitro expansion of TRM.

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The transcriptional repressor HIC1 regulates intestinal immune homeostasis

Cited by 31 publications

References 63 publications

HIC1 links retinoic acid signalling to group 3 innate lymphoid cell-dependent regulation of intestinal immunity and homeostasis

HIC1 links retinoic acid signalling to group 3 innate lymphoid cell-dependent regulation of intestinal immunity and homeostasis

Immunomodulatory Microparticles Epigenetically Modulate T Cells and Systemically Ameliorate Autoimmune Arthritis

Intestinal tissue‐resident memory T cells maintain distinct identity from circulating memory T cells after in vitro restimulation

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