Compromised Intestinal Epithelial Barrier Induces Adaptive Immune Compensation that Protects from Colitis

Manirath Khounlotham; Wooki Kim; Eric Peatman; Porfirio Nava; Oscar Medina-Contreras; Caroline Addis; Stefan Koch; Benedicte Fournier; Asma Nusrat; Timothy L. Denning; Charles A. Parkos

doi:10.1016/j.immuni.2012.06.017

Compromised Intestinal Epithelial Barrier Induces Adaptive Immune Compensation that Protects from Colitis

Manirath Khounlotham
, Wooki Kim
, Eric Peatman
, Porfirio Nava
, Oscar Medina-Contreras
, Caroline Addis
, Stefan Koch
, Benedicte Fournier
, Asma Nusrat
, Timothy L. Denning
, Charles A. Parkos

Research output: Contribution to journal › Article › peer-review

122 Citations (Scopus)

Abstract

Mice lacking junctional adhesion molecule A (JAM-A, encoded by F11r) exhibit enhanced intestinal epithelial permeability, bacterial translocation, and elevated colonic lymphocyte numbers, yet do not develop colitis. To investigate the contribution of adaptive immune compensation in response to increased intestinal epithelial permeability, we examined the susceptibility of F11r^-/-Rag1^-/- mice to acute colitis. Although negligible contributions of adaptive immunity in F11r^+/+Rag1^-/- mice were observed, F11r^-/-Rag1^-/- mice exhibited increased microflora-dependent colitis. Elimination of T cell subsets and cytokine analyses revealed a protective role for TGF-β-producing CD4⁺ T cells in F11r^-/- mice. Additionally, loss of JAM-A resulted in elevated mucosal and serum IgA that was dependent upon CD4⁺ T cells and TGF-β. Absence of IgA in F11r^+/+Igha^-/- mice did not affect disease, whereas F11r^-/-Igha^-/- mice displayed markedly increased susceptibility to acute injury-induced colitis. These data establish a role for adaptive immune-mediated protection from acute colitis under conditions of intestinal epithelial barrier compromise.

Original language	English
Pages (from-to)	563-573
Number of pages	11
Journal	Immunity
Volume	37
Issue number	3
DOIs	https://doi.org/10.1016/j.immuni.2012.06.017
Publication status	Published - 21 Sept 2012

Bibliographical note

Funding Information:
The authors thank Dr. L. Eckmann for providing Igha −/− mice, Dr. R. Ahmed and Dr. R.S. Mittler for providing GK1.5 and YTS169.4 antibodies, and Winston Lee and Christopher Capaldo for discussions. This work was supported by grants from the NIH (DK061379 and DK72564 to C.A.P., DK055679 and DK59888 to A.N., and AA017870 and AI083554 to T.L.D.), core support from a Digestive Diseases Minicenter grant (DK 064399), a Emory Egleston Children’s Research Center seed grant to T.L.D., a Crohn’s and Colitis Foundation of America Career Development Award and an AGA Foundation for Digestive Health and Nutrition Research Scholar Award to P.N., and Crohn’s and Colitis Foundation of America Research Fellowship and senior research awards to M.K. and B.F., respectively.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

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10.1016/j.immuni.2012.06.017

Cite this

@article{bc5062b2a5134a3a92d02c556aa753bc,

title = "Compromised Intestinal Epithelial Barrier Induces Adaptive Immune Compensation that Protects from Colitis",

abstract = "Mice lacking junctional adhesion molecule A (JAM-A, encoded by F11r) exhibit enhanced intestinal epithelial permeability, bacterial translocation, and elevated colonic lymphocyte numbers, yet do not develop colitis. To investigate the contribution of adaptive immune compensation in response to increased intestinal epithelial permeability, we examined the susceptibility of F11r-/-Rag1-/- mice to acute colitis. Although negligible contributions of adaptive immunity in F11r+/+Rag1-/- mice were observed, F11r-/-Rag1-/- mice exhibited increased microflora-dependent colitis. Elimination of T cell subsets and cytokine analyses revealed a protective role for TGF-β-producing CD4+ T cells in F11r-/- mice. Additionally, loss of JAM-A resulted in elevated mucosal and serum IgA that was dependent upon CD4+ T cells and TGF-β. Absence of IgA in F11r+/+Igha-/- mice did not affect disease, whereas F11r-/-Igha-/- mice displayed markedly increased susceptibility to acute injury-induced colitis. These data establish a role for adaptive immune-mediated protection from acute colitis under conditions of intestinal epithelial barrier compromise.",

author = "Manirath Khounlotham and Wooki Kim and Eric Peatman and Porfirio Nava and Oscar Medina-Contreras and Caroline Addis and Stefan Koch and Benedicte Fournier and Asma Nusrat and Denning, \{Timothy L.\} and Parkos, \{Charles A.\}",

note = "Funding Information: The authors thank Dr. L. Eckmann for providing Igha −/− mice, Dr. R. Ahmed and Dr. R.S. Mittler for providing GK1.5 and YTS169.4 antibodies, and Winston Lee and Christopher Capaldo for discussions. This work was supported by grants from the NIH (DK061379 and DK72564 to C.A.P., DK055679 and DK59888 to A.N., and AA017870 and AI083554 to T.L.D.), core support from a Digestive Diseases Minicenter grant (DK 064399), a Emory Egleston Children{\textquoteright}s Research Center seed grant to T.L.D., a Crohn{\textquoteright}s and Colitis Foundation of America Career Development Award and an AGA Foundation for Digestive Health and Nutrition Research Scholar Award to P.N., and Crohn{\textquoteright}s and Colitis Foundation of America Research Fellowship and senior research awards to M.K. and B.F., respectively.",

year = "2012",

month = sep,

day = "21",

doi = "10.1016/j.immuni.2012.06.017",

language = "English",

volume = "37",

pages = "563--573",

journal = "Immunity",

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T1 - Compromised Intestinal Epithelial Barrier Induces Adaptive Immune Compensation that Protects from Colitis

AU - Khounlotham, Manirath

AU - Kim, Wooki

AU - Peatman, Eric

AU - Nava, Porfirio

AU - Medina-Contreras, Oscar

AU - Addis, Caroline

AU - Koch, Stefan

AU - Fournier, Benedicte

AU - Nusrat, Asma

AU - Denning, Timothy L.

AU - Parkos, Charles A.

N1 - Funding Information: The authors thank Dr. L. Eckmann for providing Igha −/− mice, Dr. R. Ahmed and Dr. R.S. Mittler for providing GK1.5 and YTS169.4 antibodies, and Winston Lee and Christopher Capaldo for discussions. This work was supported by grants from the NIH (DK061379 and DK72564 to C.A.P., DK055679 and DK59888 to A.N., and AA017870 and AI083554 to T.L.D.), core support from a Digestive Diseases Minicenter grant (DK 064399), a Emory Egleston Children’s Research Center seed grant to T.L.D., a Crohn’s and Colitis Foundation of America Career Development Award and an AGA Foundation for Digestive Health and Nutrition Research Scholar Award to P.N., and Crohn’s and Colitis Foundation of America Research Fellowship and senior research awards to M.K. and B.F., respectively.

PY - 2012/9/21

Y1 - 2012/9/21

N2 - Mice lacking junctional adhesion molecule A (JAM-A, encoded by F11r) exhibit enhanced intestinal epithelial permeability, bacterial translocation, and elevated colonic lymphocyte numbers, yet do not develop colitis. To investigate the contribution of adaptive immune compensation in response to increased intestinal epithelial permeability, we examined the susceptibility of F11r-/-Rag1-/- mice to acute colitis. Although negligible contributions of adaptive immunity in F11r+/+Rag1-/- mice were observed, F11r-/-Rag1-/- mice exhibited increased microflora-dependent colitis. Elimination of T cell subsets and cytokine analyses revealed a protective role for TGF-β-producing CD4+ T cells in F11r-/- mice. Additionally, loss of JAM-A resulted in elevated mucosal and serum IgA that was dependent upon CD4+ T cells and TGF-β. Absence of IgA in F11r+/+Igha-/- mice did not affect disease, whereas F11r-/-Igha-/- mice displayed markedly increased susceptibility to acute injury-induced colitis. These data establish a role for adaptive immune-mediated protection from acute colitis under conditions of intestinal epithelial barrier compromise.

AB - Mice lacking junctional adhesion molecule A (JAM-A, encoded by F11r) exhibit enhanced intestinal epithelial permeability, bacterial translocation, and elevated colonic lymphocyte numbers, yet do not develop colitis. To investigate the contribution of adaptive immune compensation in response to increased intestinal epithelial permeability, we examined the susceptibility of F11r-/-Rag1-/- mice to acute colitis. Although negligible contributions of adaptive immunity in F11r+/+Rag1-/- mice were observed, F11r-/-Rag1-/- mice exhibited increased microflora-dependent colitis. Elimination of T cell subsets and cytokine analyses revealed a protective role for TGF-β-producing CD4+ T cells in F11r-/- mice. Additionally, loss of JAM-A resulted in elevated mucosal and serum IgA that was dependent upon CD4+ T cells and TGF-β. Absence of IgA in F11r+/+Igha-/- mice did not affect disease, whereas F11r-/-Igha-/- mice displayed markedly increased susceptibility to acute injury-induced colitis. These data establish a role for adaptive immune-mediated protection from acute colitis under conditions of intestinal epithelial barrier compromise.

UR - https://www.scopus.com/pages/publications/84866523733

U2 - 10.1016/j.immuni.2012.06.017

DO - 10.1016/j.immuni.2012.06.017

M3 - Article

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AN - SCOPUS:84866523733

SN - 1074-7613

VL - 37

SP - 563

EP - 573

JO - Immunity

JF - Immunity

IS - 3

ER -

Compromised Intestinal Epithelial Barrier Induces Adaptive Immune Compensation that Protects from Colitis

Abstract

Bibliographical note

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