Citrobacter rodentium Infection Induces Persistent Molecular Changes and Interferon Gamma-Dependent Major Histocompatibility Complex Class II Expression in the Colonic Epithelium

Mullineaux-Sanders, Caroline; Kozik, Zuzanna; Sanchez‐Garrido, Julia; Hopkins, Eve G D; Choudhary, Jyoti; Frankel, Gad

doi:10.1128/mbio.03233-21

Cited by 8 publications

(18 citation statements)

References 52 publications

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“…Comparison of the gene expression profiles of DCC and PCC cells from mid-distal colons of WT mice by scRNAseq indicated that this was indeed the case. While both DCCs and PCCs downregulated a considerable number of genes during C.r infection (e.g., Car4, Slc26a3, and several differentially expressed solute carrier genes)-indicating that both colonocyte subsets sensed the pathogen and altered their response 53,54,94,95 , a preponderance of genes that we had previously reported as contingent on T cell-derived IL-22 4 were specifically upregulated in DCCs (Fig. 3a,b and Extended Data Fig.…”

Section: Proximal and Distal Colonocytes Respond Differentially To T ...mentioning

confidence: 71%

“…1 and 3d). These subsets derive from distinct early progenitors but their gene expression profiles identified them as members of the absorptive lineage, with both subsets expressing Car4, Slc26a3 53,54 , and cell-surface mucins Muc3 and Muc13 that are main components of the protective glycocalyx layer that lies between goblet cell-derived secreted mucins (e.g., Muc2) and underlying colonocytes 55,56 (Fig. 1a and Extended Data Fig.…”

Section: Single-cell Transcriptomics Identify Two Major Subsets Of Ab...mentioning

confidence: 99%

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A novel subset of colonocytes targeted by Citrobacter rodentium elicits epithelial MHCII-restricted help from CD4 T cells

Weaver

Zindl

Wilson

et al. 2023

Preprint

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Interleukin (IL)-22 plays a non-redundant role in immune defense of the intestinal barrier1–3. We recently discovered an indispensable role for T cells, but not ILCs, in sustaining IL-22 signaling required for protection of colonic crypts against invasion during infection by the enteropathogen, Citrobacter rodentium (C.r)4. However, identification of the intestinal epithelial cell (IEC) subsets targeted by T cell-derived IL-22 and how T cell-derived IL-22 sustains activation in IECs are undefined. Here, we identify a novel subset of absorptive IECs in the mid-distal colon that are differentially targeted by C.r and are differentially responsive to IL-22 signaling. Importantly, MHCII expression by these colonocytes was required to elicit T cell-activated IL-22 signaling necessary to resist C.r invasion. Our findings explain the basis for the regionalization of the host response to C.r and demonstrate that epithelial cells must elicit MHCII-dependent help from IL-22–producing T cells to orchestrate immune protection in the intestines.

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Section: Proximal and Distal Colonocytes Respond Differentially To T ...mentioning

confidence: 71%

Section: Single-cell Transcriptomics Identify Two Major Subsets Of Ab...mentioning

confidence: 99%

A novel subset of colonocytes targeted by Citrobacter rodentium elicits epithelial MHCII-restricted help from CD4 T cells

Weaver

Zindl

Wilson

et al. 2023

Preprint

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“…It is not clear whether the conflicting study 34 performed individual validation to circumvent this issue, but it is notable that mice lacking secretory IgA do not succumb to C. rodentium infection 35,36 , whereas complete MHC II KO mice do 37 . Furthermore, although IFN-γ -/mice are unable to upregulate MHC II on colonic IECs during C. rodentium infection, they did not exhibit any mortality 38 . Taken together, these results provide a plausible explanation for differing results and support our conclusions that colonic IEC MHC II expression has little impact on C. rodentium induced intestinal inflammation and is not required for survival from this A/E pathogen.…”

Section: Discussionmentioning

confidence: 89%

MHC class II antigen presentation by intestinal epithelial cells fine-tunes bacteria-reactive CD4 T cell responses

Heuberger

Janney

Ilott

et al. 2023

Preprint

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Although intestinal epithelial cells (IECs) can express major histocompatibility complex class II (MHC II), especially during intestinal inflammation, it remains unclear if antigen presentation by IECs favours pro- or anti-inflammatory CD4+ T cell responses. Using selective gene ablation of MHC II in IECs and IEC organoid cultures, we assessed the impact of MHC II expression by IECs on CD4+ T cell responses and disease outcomes in response to enteric bacterial pathogens. We found that intestinal bacterial infections elicit inflammatory cues that greatly increase expression of MHC II processing and presentation molecules in colonic IECs. Whilst IEC MHC II expression had little impact on disease severity following Citrobacter rodentium or Helicobacter hepaticus infection, using a colonic IEC organoid-CD4+ T cell co-culture system, we demonstrate that IECs can activate antigen-specific CD4+ T cells in an MHC II-dependent manner, modulating both regulatory and effector Th cell subsets. Furthermore, we assessed adoptively transferred H. hepaticus-specific CD4+ T cells during intestinal inflammation in vivo and report that IEC MHC II expression dampens pro-inflammatory effector Th cells. Our findings indicate that IECs can function as non-conventional antigen presenting cells and that IEC MHC II expression fine-tunes local effector CD4+ T cell responses during intestinal inflammation.

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“…Although antigenic priming of naive CD4 T cells to Cr is thought to occur in lymphoid tissues by type 2 conventional dendritic cells 45 , it is unclear whether Cr antigens can be presented by IECs to directly recruit CD4 T cell help 46 . Previous studies have found that IECs begin to upregulate MHCII and other components of the class II antigen processing and presentation (APP) system coincident with the influx of effector CD4 T cells into the infected mid–distal colon, leading to MHCII expression by the majority of IECs later in infection 4 , 16 , 46 , 47 . This coincided with sustained STAT3 activation in IECs driven by T cell-derived IL-22 signalling 4 , 16 .…”

Section: Epithelial Mhcii Is Required To Recruit T-cell Helpmentioning

confidence: 99%

Distal colonocytes targeted by C. rodentium recruit T-cell help for barrier defence

Zindl,

Wilson,

Chadha

et al. 2024

Nature

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Interleukin 22 (IL-22) has a non-redundant role in immune defence of the intestinal barrier1–3. T cells, but not innate lymphoid cells, have an indispensable role in sustaining the IL-22 signalling that is required for the protection of colonic crypts against invasion during infection by the enteropathogen Citrobacter rodentium4 (Cr). However, the intestinal epithelial cell (IEC) subsets targeted by T cell-derived IL-22, and how T cell-derived IL-22 sustains activation in IECs, remain undefined. Here we identify a subset of absorptive IECs in the mid–distal colon that are specifically targeted by Cr and are differentially responsive to IL-22 signalling. Major histocompatibility complex class II (MHCII) expression by these colonocytes was required to elicit sustained IL-22 signalling from Cr-specific T cells, which was required to restrain Cr invasion. Our findings explain the basis for the regionalization of the host response to Cr and demonstrate that epithelial cells must elicit MHCII-dependent help from IL-22–producing T cells to orchestrate immune protection in the intestine.

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Citrobacter rodentium Infection Induces Persistent Molecular Changes and Interferon Gamma-Dependent Major Histocompatibility Complex Class II Expression in the Colonic Epithelium

Abstract: Mucosal surfaces respond to infection by mounting an array of metabolic, inflammatory, and tissue repair responses. While these have been well studied during acute infection, less is known about tissue recovery after pathogen clearance.

Cited by 8 publications

References 52 publications

A novel subset of colonocytes targeted by Citrobacter rodentium elicits epithelial MHCII-restricted help from CD4 T cells

A novel subset of colonocytes targeted by Citrobacter rodentium elicits epithelial MHCII-restricted help from CD4 T cells

MHC class II antigen presentation by intestinal epithelial cells fine-tunes bacteria-reactive CD4 T cell responses

Distal colonocytes targeted by C. rodentium recruit T-cell help for barrier defence

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