CTLA-4 expressing innate lymphoid cells modulate mucosal homeostasis in a microbiota dependent manner

Jonathan W Lo; Jan-Hendrik Schroeder; Luke B Roberts; Rami Mohamed; Domenico Cozzetto; Gordon Beattie; Omer S Omer; Ellen M Ross; Frank Heuts; Geraldine M Jowett; Emily Read; Matthew Madgwick; Joana F Neves; Tamas Korcsmaros; Richard G Jenner; Lucy S K Walker; Nick Powell; Graham M Lord

doi:10.1038/s41467-024-51719-6

CTLA-4 expressing innate lymphoid cells modulate mucosal homeostasis in a microbiota dependent manner

Jonathan W Lo, Jan-Hendrik Schroeder, Luke B Roberts, Rami Mohamed, Domenico Cozzetto, Gordon Beattie, Omer S Omer, Ellen M Ross, Frank Heuts, Geraldine M Jowett, Emily Read, Matthew Madgwick, Joana F Neves, Tamas Korcsmaros, Richard G Jenner, Lucy S K Walker, Nick Powell, Graham M Lord

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

Abstract

The maintenance of intestinal homeostasis is a fundamental process critical for organismal integrity. Sitting at the interface of the gut microbiome and mucosal immunity, adaptive and innate lymphoid populations regulate the balance between commensal micro-organisms and pathogens. Checkpoint inhibitors, particularly those targeting the CTLA-4 pathway, disrupt this fine balance and can lead to inflammatory bowel disease and immune checkpoint colitis. Here, we show that CTLA-4 is expressed by innate lymphoid cells and that its expression is regulated by ILC subset-specific cytokine cues in a microbiota-dependent manner. Genetic deletion or antibody blockade of CTLA-4 in multiple in vivo models of colitis demonstrates that this pathway plays a key role in intestinal homeostasis. Lastly, we have found that this observation is conserved in human IBD. We propose that this population of CTLA-4-positive ILC may serve as an important target for the treatment of idiopathic and iatrogenic intestinal inflammation.

Original language	English
Article number	9520
Pages (from-to)	9520
Journal	Nature Communications
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41467-024-51719-6
Publication status	Published - 4 Nov 2024

Keywords

Animals
CTLA-4 Antigen/metabolism
Immunity, Innate
Homeostasis
Humans
Mice
Intestinal Mucosa/immunology
Gastrointestinal Microbiome/immunology
Lymphocytes/immunology
Colitis/immunology
Mice, Inbred C57BL
Female
Inflammatory Bowel Diseases/immunology
Mice, Knockout
Male
Cytokines/metabolism
Disease Models, Animal
Immunity, Mucosal

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10.1038/s41467-024-51719-6

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Lo, J. W., Schroeder, J.-H., Roberts, L. B., Mohamed, R., Cozzetto, D., Beattie, G., Omer, O. S., Ross, E. M., Heuts, F., Jowett, G. M., Read, E., Madgwick, M., Neves, J. F., Korcsmaros, T., Jenner, R. G., Walker, L. S. K., Powell, N., & Lord, G. M. (2024). CTLA-4 expressing innate lymphoid cells modulate mucosal homeostasis in a microbiota dependent manner. Nature Communications, 15(1), 9520. Article 9520. https://doi.org/10.1038/s41467-024-51719-6

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title = "CTLA-4 expressing innate lymphoid cells modulate mucosal homeostasis in a microbiota dependent manner",

abstract = "The maintenance of intestinal homeostasis is a fundamental process critical for organismal integrity. Sitting at the interface of the gut microbiome and mucosal immunity, adaptive and innate lymphoid populations regulate the balance between commensal micro-organisms and pathogens. Checkpoint inhibitors, particularly those targeting the CTLA-4 pathway, disrupt this fine balance and can lead to inflammatory bowel disease and immune checkpoint colitis. Here, we show that CTLA-4 is expressed by innate lymphoid cells and that its expression is regulated by ILC subset-specific cytokine cues in a microbiota-dependent manner. Genetic deletion or antibody blockade of CTLA-4 in multiple in vivo models of colitis demonstrates that this pathway plays a key role in intestinal homeostasis. Lastly, we have found that this observation is conserved in human IBD. We propose that this population of CTLA-4-positive ILC may serve as an important target for the treatment of idiopathic and iatrogenic intestinal inflammation.",

keywords = "Animals, CTLA-4 Antigen/metabolism, Immunity, Innate, Homeostasis, Humans, Mice, Intestinal Mucosa/immunology, Gastrointestinal Microbiome/immunology, Lymphocytes/immunology, Colitis/immunology, Mice, Inbred C57BL, Female, Inflammatory Bowel Diseases/immunology, Mice, Knockout, Male, Cytokines/metabolism, Disease Models, Animal, Immunity, Mucosal",

author = "Lo, {Jonathan W} and Jan-Hendrik Schroeder and Roberts, {Luke B} and Rami Mohamed and Domenico Cozzetto and Gordon Beattie and Omer, {Omer S} and Ross, {Ellen M} and Frank Heuts and Jowett, {Geraldine M} and Emily Read and Matthew Madgwick and Neves, {Joana F} and Tamas Korcsmaros and Jenner, {Richard G} and Walker, {Lucy S K} and Nick Powell and Lord, {Graham M}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

month = nov,

day = "4",

doi = "10.1038/s41467-024-51719-6",

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Lo, JW, Schroeder, J-H , Roberts, LB , Mohamed, R, Cozzetto, D, Beattie, G, Omer, OS, Ross, EM, Heuts, F, Jowett, GM , Read, E, Madgwick, M, Neves, JF, Korcsmaros, T, Jenner, RG, Walker, LSK, Powell, N & Lord, GM 2024, 'CTLA-4 expressing innate lymphoid cells modulate mucosal homeostasis in a microbiota dependent manner', Nature Communications, vol. 15, no. 1, 9520, pp. 9520. https://doi.org/10.1038/s41467-024-51719-6

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AU - Lo, Jonathan W

AU - Schroeder, Jan-Hendrik

AU - Roberts, Luke B

AU - Mohamed, Rami

AU - Cozzetto, Domenico

AU - Beattie, Gordon

AU - Omer, Omer S

AU - Ross, Ellen M

AU - Heuts, Frank

AU - Jowett, Geraldine M

AU - Read, Emily

AU - Madgwick, Matthew

AU - Neves, Joana F

AU - Korcsmaros, Tamas

AU - Jenner, Richard G

AU - Walker, Lucy S K

AU - Powell, Nick

AU - Lord, Graham M

N1 - Publisher Copyright: © The Author(s) 2024.

PY - 2024/11/4

Y1 - 2024/11/4

N2 - The maintenance of intestinal homeostasis is a fundamental process critical for organismal integrity. Sitting at the interface of the gut microbiome and mucosal immunity, adaptive and innate lymphoid populations regulate the balance between commensal micro-organisms and pathogens. Checkpoint inhibitors, particularly those targeting the CTLA-4 pathway, disrupt this fine balance and can lead to inflammatory bowel disease and immune checkpoint colitis. Here, we show that CTLA-4 is expressed by innate lymphoid cells and that its expression is regulated by ILC subset-specific cytokine cues in a microbiota-dependent manner. Genetic deletion or antibody blockade of CTLA-4 in multiple in vivo models of colitis demonstrates that this pathway plays a key role in intestinal homeostasis. Lastly, we have found that this observation is conserved in human IBD. We propose that this population of CTLA-4-positive ILC may serve as an important target for the treatment of idiopathic and iatrogenic intestinal inflammation.

AB - The maintenance of intestinal homeostasis is a fundamental process critical for organismal integrity. Sitting at the interface of the gut microbiome and mucosal immunity, adaptive and innate lymphoid populations regulate the balance between commensal micro-organisms and pathogens. Checkpoint inhibitors, particularly those targeting the CTLA-4 pathway, disrupt this fine balance and can lead to inflammatory bowel disease and immune checkpoint colitis. Here, we show that CTLA-4 is expressed by innate lymphoid cells and that its expression is regulated by ILC subset-specific cytokine cues in a microbiota-dependent manner. Genetic deletion or antibody blockade of CTLA-4 in multiple in vivo models of colitis demonstrates that this pathway plays a key role in intestinal homeostasis. Lastly, we have found that this observation is conserved in human IBD. We propose that this population of CTLA-4-positive ILC may serve as an important target for the treatment of idiopathic and iatrogenic intestinal inflammation.

KW - Animals

KW - CTLA-4 Antigen/metabolism

KW - Immunity, Innate

KW - Homeostasis

KW - Humans

KW - Mice

KW - Intestinal Mucosa/immunology

KW - Gastrointestinal Microbiome/immunology

KW - Lymphocytes/immunology

KW - Colitis/immunology

KW - Mice, Inbred C57BL

KW - Female

KW - Inflammatory Bowel Diseases/immunology

KW - Mice, Knockout

KW - Male

KW - Cytokines/metabolism

KW - Disease Models, Animal

KW - Immunity, Mucosal

UR - http://www.scopus.com/inward/record.url?scp=85208517337&partnerID=8YFLogxK

U2 - 10.1038/s41467-024-51719-6

DO - 10.1038/s41467-024-51719-6

M3 - Article

C2 - 39496592

SN - 2041-1723

VL - 15

SP - 9520

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 9520

ER -

CTLA-4 expressing innate lymphoid cells modulate mucosal homeostasis in a microbiota dependent manner

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