How T cell-derived interleukin-22 promotes antibacterial defense of
colonic crypts
Date:
April 8, 2022
Source:
University of Alabama at Birmingham
Summary:
Intestinal epithelial cells line the inner wall of the gut, creating
a barrier to dangerous bacteria like enteropathogenic E. coli that
seek to attach and efface that barrier, causing diarrhea. Such
pathogens pose significant risks to human health and cause infant
death in developing countries. A new study shows how two types of
immune cells -- one a part of the innate immune system and the
other a part of the adaptive immune system -- play distinct and
indispensable roles to defend that barrier.
FULL STORY ========================================================================== Intestinal epithelial cells line the inner wall of the gut, creating a
barrier to dangerous bacteria like enteropathogenic E. colithat seek to
attach and efface that barrier, causing diarrhea. Such pathogens pose significant risks to human health and cause infant death in developing countries.
==========================================================================
In a study published in the journal Immunity, Carlene L. Zindl, Ph.D.,
and Casey T. Weaver, M.D., of the University of Alabama at Birmingham Department of Pathology show how two types of immune cells -- one a part
of the innate immune system and the other a part of the adaptive immune
system -- play distinct and indispensable roles to defend that barrier.
"In this study, we define a nonredundant role for interleukin-22-producing
T cells in antibacterial defense of colonic crypts," Weaver said. "Our
findings address a central, unresolved issue regarding the coordination
of innate and adaptive immunity and specialization of innate lymphoid
cells, or ILCs, and CD4 T cells. Since the discovery of ILC subsets and appreciation of their functional parallel with T cell subsets, it has
been unclear what functions are unique to each immune cell population."
The study used mice with bacterial infection of the colon by Citrobacter rodentium, which models human disease caused by enteropathogenic
and enterohemorrhagic E. coli. Colons of mice and humans have surface intestinal epithelial cells, or surface IECs, that face the lumen of the
colon and line the mouths of colonic crypts. The colonic crypts are the numerous tiny indentations in the colon that are shaped like thick-walled
test tubes; at the bottom of each crypt are stem cells that give rise
to all new IEC subsets.
Each crypt is only about 75 to 110 cells deep and 23 cells in
circumference, and the human colon has about 9,950,000 crypts. Crypt
IECs line each crypt.
Interleukin-22, or IL-22, is a cytokine signaling protein produced by
cells to initiate an immune response. The UAB researchers developed
mice that have a reporter gene in IL-22, so they could tell which cells produced IL-22. They also were able to target a deficiency of IL-22 to different immune cell populations, to learn the effect of that loss of
IL-22 production in a subset of cells upon the progress of C. rodentium infections.
==========================================================================
The researchers found that the ILC3 subset of innate immune cells
were the dominant IL-22-positive cells at steady state, before any
infection. During early infection with C. rodentium, days 3 to 6, ILC3s produced the greatest amount of IL-22. During late infection, days 7 to
14, T cells had increased 50- fold in number and were the dominant IL-22 producers. Furthermore, the two types of cells had distinct microanatomic niches -- ILC3s were confined to small, isolated lymphoid follicles,
at some distance from crypts, and they did not increase in number during infection. The rapidly growing T cells surrounded the crypts, in closer proximity to IECs compared to ILC3s.
By knocking out IL-22 production in both or either of the immune cell
types, researchers could discern their particular roles -- both by
visualizing infection in living mice using a bioluminescent strain of
C. rodentium, and by looking at which IECs were activated by IL-22.
In mice with intact immune systems, some growth of C. rodentium
in the colon was seen at days 3 to 7; but the mice survived the
infection. In mice without IL-22 production by both ILC3s and T cells,
heavy C. rodentium infection was seen at days 3 to 7, and all the mice thereafter succumbed to the infection.
Mice that had no IL-22 production by the ILC3s, but still maintained
IL-22 production in T cells, began to succumb to infection as quickly
as the total IL-22 knockout mice; but 40 percent survived, presumably
rescued by later IL-22 production from the T cells. Mice with loss
of IL-22 production only in the T cells began to succumb to infection
at a later time than the other two mouse strains, and they showed 60
percent survival.
"These data establish that innate cell-derived IL-22 acts to limit
C. rodentium colonization during the early phase of infection," said
Weaver, the Wyatt and Susan Haskell Chair of Medical Excellence in
Pathology, "but is unable to compensate for T cell-derived IL-22 in
bacterial restraint and host protection later." Microscopic examination
of colon sections showed that mice with intact immune systems had
bacterial attachment to surface IECs at days 4 to 9, but no bacterial
growth inside the crypts. In mice without IL-22 production by all immune
cells or by T cells only, heavy infection was seen inside the crypt lumen,
and C. rodentium was attached to crypt IECs by day 9.
==========================================================================
When the IL-22 produced by the immune cells binds to IECs, it activates
the STAT3 signaling pathway in the target cells, which in turn activates
or represses specific genes in the target cells.
Microscopic examination of colon sections stained for STAT3 activation
showed that, despite their critical role in restraining bacterial
colonization over the early course of enteropathogenic bacterial
infection, ILC3s only induced weak STAT3 signaling, and that signaling was limited to the surface IECs. In contrast, T cells contributed to colon
barrier defense by delivering IL-22 to both crypt IECs and surface IECs
as an infection progressed, inducing robust, sustained STAT3 signaling
in both IEC populations. "Our data determine that 'specialized' T
cell immunity is required for protection of the colonic crypts during
C. rodentium infection," Zindl said. "This may reflect the ability of
T cells, unlike ILC3s, to migrate to the crypt epithelium and engage in
direct contact with IECs via peptide-MHC and/or surface adhesion molecule interactions." Zindl is a UAB Scientist I and the lead researcher in
the study.
The resulting gene expression changes in the IECs included
heightened expression of messenger RNAs for antimicrobial peptides, neutrophil-recruiting chemokines and enzymes that altered the protective
mucins produced by colon goblet cells and enterocytes. All of these
help fight a bacterial infection. In contrast, interferon gamma-induced proinflammatory genes were repressed. "These data reveal a dual role
of T cell-derived IL-22," Zindl said, "in both promoting antibacterial
defense of the crypts and limiting tissue damage caused by uncontrolled
IEC and immune cell activation." "Our findings demonstrate spatiotemporal differences in the production and action of IL-22 by ILCs and T cells
during infection," Weaver said, "and they reveal an indispensable role
for IL-22-producing T cells in the protection of the intestinal crypts."
========================================================================== Story Source: Materials provided by
University_of_Alabama_at_Birmingham. Original written by Jeff
Hansen. Note: Content may be edited for style and length.
========================================================================== Journal Reference:
1. Carlene L. Zindl, Steven J. Witte, Vincent A. Laufer, Min Gao,
Zongliang
Yue, Karen M. Janowski, Baiyi Cai, Blake F. Frey, Daniel
J. Silberger, Stacey N. Harbour, Jeffrey R. Singer, Henrietta
Turner, Frances E. Lund, Bruce A. Vallance, Alexander F. Rosenberg,
Trenton R. Schoeb, Jake Y.
Chen, Robin D. Hatton, Casey T. Weaver. A nonredundant role for T
cell- derived interleukin 22 in antibacterial defense of colonic
crypts.
Immunity, 2022; 55 (3): 494 DOI: 10.1016/j.immuni.2022.02.003 ==========================================================================
Link to news story:
https://www.sciencedaily.com/releases/2022/04/220408131748.htm
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