Goblet Cell Derived RELM-β Recruits CD4+ T Cells during Infectious Colitis to Promote Protective Intestinal Epithelial Cell Proliferation.
Enterohemorrhagic Escherichia coli and related food and waterborne pathogens pose significant threats to human health. These attaching/effacing microbes infect the apical surface of intestinal epithelial cells (IEC), causing severe diarrheal disease. Colonizing the intestinal luminal surface helps segregate these microbes from most host inflammatory responses. Based on studies using Citrobacter rodentium, a related mouse pathogen, we speculate that hosts rely on immune-mediated changes in IEC, including goblet cells to defend against these pathogens. These changes include a CD4+ T cell-dependent increase in IEC proliferation to replace infected IEC, as well as altered production of the goblet cell-derived mucin Muc2. Another goblet cell mediator, REsistin-Like Molecule (RELM)-β is strongly induced within goblet cells during C. rodentium infection, and was detected in the stool as well as serum. Despite its dramatic induction, RELM-β's role in host defense is unclear. Thus, wildtype and RELM-β gene deficient mice (Retnlb-/-) were orally infected with C. rodentium. While their C. rodentium burdens were only modestly elevated, infected Retnlb-/- mice suffered increased mortality and mucosal ulceration due to deep pathogen penetration of colonic crypts. Immunostaining for Ki67 and BrDU revealed Retnlb-/- mice were significantly impaired in infection-induced IEC hyper-proliferation. Interestingly, exposure to RELM-β did not directly increase IEC proliferation, rather RELM-β acted as a CD4+ T cell chemoattractant. Correspondingly, Retnlb-/- mice showed impaired CD4+ T cell recruitment to their infected colons, along with reduced production of interleukin (IL)-22, a multifunctional cytokine that directly increased IEC proliferation. Enema delivery of RELM-β to Retnlb-/- mice restored CD4+ T cell recruitment, concurrently increasing IL-22 levels and IEC proliferation, while reducing mucosal pathology. These findings demonstrate that RELM-β and goblet cells play an unexpected, yet critical role in recruiting CD4+ T cells to the colon to protect against an enteric pathogen, in part via the induction of increased IEC proliferation.
Division of Gastroenterology, Department of Pediatrics, Child and Family Research Institute, Vancouver, Canada.
Kirk S B
KS
Bergstrom
Division of Gastroenterology, Department of Pediatrics, Child and Family Research Institute, Vancouver, Canada.
Vijay
V
Morampudi
Division of Gastroenterology, Department of Pediatrics, Child and Family Research Institute, Vancouver, Canada.
Justin M
JM
Chan
Division of Gastroenterology, Department of Pediatrics, Child and Family Research Institute, Vancouver, Canada.
Ganive
G
Bhinder
Division of Gastroenterology, Department of Pediatrics, Child and Family Research Institute, Vancouver, Canada.
Jennifer
J
Lau
Division of Gastroenterology, Department of Pediatrics, Child and Family Research Institute, Vancouver, Canada.
Hyungjun
H
Yang
Division of Gastroenterology, Department of Pediatrics, Child and Family Research Institute, Vancouver, Canada.
Caixia
C
Ma
Division of Gastroenterology, Department of Pediatrics, Child and Family Research Institute, Vancouver, Canada.
Tina
T
Huang
Division of Gastroenterology, Department of Pediatrics, Child and Family Research Institute, Vancouver, Canada.
Natasha
N
Ryz
Division of Gastroenterology, Department of Pediatrics, Child and Family Research Institute, Vancouver, Canada.
Ho Pan
HP
Sham
Division of Gastroenterology, Department of Pediatrics, Child and Family Research Institute, Vancouver, Canada.
Maryam
M
Zarepour
Biomedical Research Centre, University of British Columbia, Vancouver, Canada.
Colby
C
Zaph
Jill Roberts Institute for Research in Inflammatory Bowel Disease, Joan and Sanford Weill Department of Medicine, West Cornell Medical College, Cornell University, New York, New York, United States of America.
David
D
Artis
Division of Biomedical Sciences, University of California, Riverside, Riverside, California, United States of America.
Meera
M
Nair
Division of Gastroenterology, Department of Pediatrics, Child and Family Research Institute, Vancouver, Canada.
Bruce A
BA
Vallance
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation; D002469:Cell Separation; D044082:Citrobacter rodentium; D003092:Colitis / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D020397:Goblet Cells / Q000276:immunology* / Q000378:metabolism; D006729:Hormones, Ectopic / Q000276:immunology* / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D007413:Intestinal Mucosa / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction
D006729:Hormones, Ectopic; D036341:Intercellular Signaling Peptides and Proteins; C486522:Retnlb protein, mouse