TY - JOUR
T1 - Intestinal Epithelial Expression of MHCII Determines Severity of Chemical, T-Cell–Induced, and Infectious Colitis in Mice
AU - Jamwal, Deepa R.
AU - Laubitz, Daniel
AU - Harrison, Christy A.
AU - Figliuolo da Paz, Vanessa
AU - Cox, Christopher M.
AU - Wong, Rachel
AU - Midura-Kiela, Monica
AU - Gurney, Michael A.
AU - Besselsen, David G.
AU - Setty, Prashanth
AU - Lybarger, Lonnie
AU - Bhattacharya, Deepta
AU - Wilson, Jean M.
AU - Ghishan, Fayez K.
AU - Kiela, Pawel R.
N1 - Funding Information:
Funding This work was supported by National Institutes of Health (NIH) 5R01 DK109711 (Pawel R. Kiela and Fayez K. Ghishan), PANDA Endowment in Autoimmune Diseases (Pawel R. Kiela), NIH RO1 DK108701 (Jean M. Wilson), and NIH R01 AI099108 (David G. Besselsen).
Publisher Copyright:
© 2020 AGA Institute
PY - 2020/10
Y1 - 2020/10
N2 - Background & Aims: Intestinal epithelial cells (IECs) provide a barrier that separates the mucosal immune system from the luminal microbiota. IECs constitutively express low levels of major histocompatibility complex (MHC) class II proteins, which are upregulated upon exposure to interferon gamma. We investigated the effects of deleting MHCII proteins specifically in mice with infectious, dextran sodium sulfate (DSS)–, and T-cell–induced colitis. Methods: We disrupted the histocompatibility 2, class II antigen A, beta 1 gene (H2-Ab1) in IECs of C57BL/6 mice (I-AbΔIEC) or Rag1–/– mice (Rag1–/–I-AbΔIEC); we used I-AbWT mice as controls. Colitis was induced by administration of DSS, transfer of CD4+CD45RBhi T cells, or infection with Citrobacter rodentium. Colon tissues were collected and analyzed by histology, immunofluorescence, xMAP, and reverse-transcription polymerase chain reaction and organoids were generated. Microbiota (total and immunoglobulin [Ig]A-coated) in intestinal samples were analyzed by16S amplicon profiling. IgA+CD138+ plasma cells from Peyer's patches and lamina propria were analyzed by flow cytometry and IgA repertoire was determined by next-generation sequencing. Results: Mice with IEC-specific loss of MHCII (I-AbΔIEC mice) developed less severe DSS- or T-cell transfer-induced colitis than control mice. Intestinal tissues from I-AbΔIEC mice had a lower proportion of IgA-coated bacteria compared with control mice, and a reduced luminal concentration of secretory IgA (SIgA) following infection with C rodentium. There was no significant difference in the mucosal IgA repertoire of I-AbΔIEC vs control mice, but opsonization of cultured C rodentium by SIgA isolated from I-AbΔIEC mice was 50% lower than that of SIgA from mAbWT mice. Fifty percent of I-AbΔIEC mice died after infection with C rodentium, compared with none of the control mice. We observed a transient but significant expansion of the pathogen in the feces of I-AbΔIEC mice compared with I-AbWT mice. Conclusions: In mice with DSS or T-cell–induced colitis, loss of MHCII from IECs reduces but does not eliminate mucosal inflammation. However, in mice with C rodentium–induced colitis, loss of MHCII reduces bacterial clearance by decreasing binding of IgA to commensal and pathogenic bacteria.
AB - Background & Aims: Intestinal epithelial cells (IECs) provide a barrier that separates the mucosal immune system from the luminal microbiota. IECs constitutively express low levels of major histocompatibility complex (MHC) class II proteins, which are upregulated upon exposure to interferon gamma. We investigated the effects of deleting MHCII proteins specifically in mice with infectious, dextran sodium sulfate (DSS)–, and T-cell–induced colitis. Methods: We disrupted the histocompatibility 2, class II antigen A, beta 1 gene (H2-Ab1) in IECs of C57BL/6 mice (I-AbΔIEC) or Rag1–/– mice (Rag1–/–I-AbΔIEC); we used I-AbWT mice as controls. Colitis was induced by administration of DSS, transfer of CD4+CD45RBhi T cells, or infection with Citrobacter rodentium. Colon tissues were collected and analyzed by histology, immunofluorescence, xMAP, and reverse-transcription polymerase chain reaction and organoids were generated. Microbiota (total and immunoglobulin [Ig]A-coated) in intestinal samples were analyzed by16S amplicon profiling. IgA+CD138+ plasma cells from Peyer's patches and lamina propria were analyzed by flow cytometry and IgA repertoire was determined by next-generation sequencing. Results: Mice with IEC-specific loss of MHCII (I-AbΔIEC mice) developed less severe DSS- or T-cell transfer-induced colitis than control mice. Intestinal tissues from I-AbΔIEC mice had a lower proportion of IgA-coated bacteria compared with control mice, and a reduced luminal concentration of secretory IgA (SIgA) following infection with C rodentium. There was no significant difference in the mucosal IgA repertoire of I-AbΔIEC vs control mice, but opsonization of cultured C rodentium by SIgA isolated from I-AbΔIEC mice was 50% lower than that of SIgA from mAbWT mice. Fifty percent of I-AbΔIEC mice died after infection with C rodentium, compared with none of the control mice. We observed a transient but significant expansion of the pathogen in the feces of I-AbΔIEC mice compared with I-AbWT mice. Conclusions: In mice with DSS or T-cell–induced colitis, loss of MHCII from IECs reduces but does not eliminate mucosal inflammation. However, in mice with C rodentium–induced colitis, loss of MHCII reduces bacterial clearance by decreasing binding of IgA to commensal and pathogenic bacteria.
KW - Activation
KW - Antibody Production
KW - Antigen Presentation
KW - Immune Regulation
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U2 - 10.1053/j.gastro.2020.06.049
DO - 10.1053/j.gastro.2020.06.049
M3 - Article
C2 - 32589883
AN - SCOPUS:85092729946
SN - 0016-5085
VL - 159
SP - 1342-1356.e6
JO - Gastroenterology
JF - Gastroenterology
IS - 4
ER -