Duplication of the IL2RA locus causes excessive IL-2 signaling and may predispose to very early onset colitis

Maria E. Joosse; Fabienne Charbit-Henrion; Remy Boisgard; Rolien (H ).C. Raatgeep; Dicky J. Lindenbergh-Kortleve; Léa M.M. Costes; Sandrine Nugteren; Nicolas Guegan; Marianna Parlato; Sharon Veenbergen; Valérie Malan; Jan K. Nowak; Iris H.I.M. Hollink; M. Luisa Mearin; Johanna C. Escher; Nadine Cerf-Bensussan; Janneke N. Samsom

doi:10.1038/s41385-021-00423-5

Duplication of the IL2RA locus causes excessive IL-2 signaling and may predispose to very early onset colitis

Maria E. Joosse, Fabienne Charbit-Henrion, Remy Boisgard, Rolien (H ).C. Raatgeep, Dicky J. Lindenbergh-Kortleve, Léa M.M. Costes, Sandrine Nugteren, Nicolas Guegan, Marianna Parlato, Sharon Veenbergen, Valérie Malan, Jan K. Nowak, Iris H.I.M. Hollink, M. Luisa Mearin, Johanna C. Escher, Nadine Cerf-Bensussan, Janneke N. Samsom^*

^*Corresponding author for this work

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

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Abstract

Single genetic mutations predispose to very early onset inflammatory bowel disease (VEO-IBD). Here, we identify a de novo duplication of the 10p15.1 chromosomal region, including the IL2RA locus, in a 2-year-old girl with treatment-resistant pancolitis that was brought into remission by colectomy. Strikingly, after colectomy while the patient was in clinical remission and without medication, the peripheral blood CD4:CD8 ratio was constitutively high and CD25 expression was increased on circulating effector memory, Foxp3⁺, and Foxp3^neg CD4⁺ T cells compared to healthy controls. This high CD25 expression increased IL-2 signaling, potentiating CD4⁺ T-cell-derived IFNγ secretion after T-cell receptor (TCR) stimulation. Restoring CD25 expression using the JAK1/3-inhibitor tofacitinib controlled TCR-induced IFNγ secretion in vitro. As diseased colonic tissue, but not the unaffected duodenum, contained mainly CD4⁺ T cells with a prominent IFNγ-signature, we hypothesize that local microbial stimulation may have initiated colonic disease. Overall, we identify that duplication of the IL2RA locus can associate with VEO-IBD and suggest that increased IL-2 signaling predisposes to colonic intestinal inflammation.

Original language	English
Pages (from-to)	1172-1182
Number of pages	11
Journal	Mucosal Immunology
Volume	14
Issue number	5
Early online date	5 Jul 2021
DOIs	https://doi.org/10.1038/s41385-021-00423-5
Publication status	Published - Sept 2021

Bibliographical note

Funding Information:
The authors declare no competing financial interests. This work was supported by ERC-2013-AdG-339407-IMMUNOBIOTA and Inserm grant n°ANR-10-LABX-62-IBEID to N.C.B. M.J. was supported by the Netherlands Organization for Scientific Research grant 2013/09420/BOO. L.M.M.C. was funded by SSWO grants (SSWO 608, S16-23) and a research fellowship from the Dutch Sophia Research Foundation. S.V. was funded by the Dutch Sophia Research Foundation SSWO grant (S14-17). J.K.N. was supported by a grant from the Polish National Science Centre (2015/16/T/NZ5/ 00168). F.C.H. was supported by a fellowship from INSERM and acknowledges the members of the GENIUS group (GENetically ImmUne mediated enteropathieS) from ESPGHAN (European Society for Paediatric Gastroenterology, Hepatology and Nutrition), www.genius-group.org.

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© 2021, The Author(s).

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Duplication of the IL2RA locus causes excessive IL-2 signaling and may predispose to very early onset colitisFinal published version, 6.25 MBLicence: CC BY

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Joosse, M. E., Charbit-Henrion, F., Boisgard, R., Raatgeep, R., Lindenbergh-Kortleve, D. J., Costes, L. M. M., Nugteren, S., Guegan, N., Parlato, M., Veenbergen, S., Malan, V., Nowak, J. K., Hollink, I. H. I. M., Mearin, M. L., Escher, J. C., Cerf-Bensussan, N., & Samsom, J. N. (2021). Duplication of the IL2RA locus causes excessive IL-2 signaling and may predispose to very early onset colitis. Mucosal Immunology, 14(5), 1172-1182. https://doi.org/10.1038/s41385-021-00423-5

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title = "Duplication of the IL2RA locus causes excessive IL-2 signaling and may predispose to very early onset colitis",

abstract = "Single genetic mutations predispose to very early onset inflammatory bowel disease (VEO-IBD). Here, we identify a de novo duplication of the 10p15.1 chromosomal region, including the IL2RA locus, in a 2-year-old girl with treatment-resistant pancolitis that was brought into remission by colectomy. Strikingly, after colectomy while the patient was in clinical remission and without medication, the peripheral blood CD4:CD8 ratio was constitutively high and CD25 expression was increased on circulating effector memory, Foxp3+, and Foxp3neg CD4+ T cells compared to healthy controls. This high CD25 expression increased IL-2 signaling, potentiating CD4+ T-cell-derived IFNγ secretion after T-cell receptor (TCR) stimulation. Restoring CD25 expression using the JAK1/3-inhibitor tofacitinib controlled TCR-induced IFNγ secretion in vitro. As diseased colonic tissue, but not the unaffected duodenum, contained mainly CD4+ T cells with a prominent IFNγ-signature, we hypothesize that local microbial stimulation may have initiated colonic disease. Overall, we identify that duplication of the IL2RA locus can associate with VEO-IBD and suggest that increased IL-2 signaling predisposes to colonic intestinal inflammation.",

author = "Joosse, {Maria E.} and Fabienne Charbit-Henrion and Remy Boisgard and Raatgeep, {Rolien (H ).C.} and Lindenbergh-Kortleve, {Dicky J.} and Costes, {L{\'e}a M.M.} and Sandrine Nugteren and Nicolas Guegan and Marianna Parlato and Sharon Veenbergen and Val{\'e}rie Malan and Nowak, {Jan K.} and Hollink, {Iris H.I.M.} and Mearin, {M. Luisa} and Escher, {Johanna C.} and Nadine Cerf-Bensussan and Samsom, {Janneke N.}",

note = "Funding Information: The authors declare no competing financial interests. This work was supported by ERC-2013-AdG-339407-IMMUNOBIOTA and Inserm grant n°ANR-10-LABX-62-IBEID to N.C.B. M.J. was supported by the Netherlands Organization for Scientific Research grant 2013/09420/BOO. L.M.M.C. was funded by SSWO grants (SSWO 608, S16-23) and a research fellowship from the Dutch Sophia Research Foundation. S.V. was funded by the Dutch Sophia Research Foundation SSWO grant (S14-17). J.K.N. was supported by a grant from the Polish National Science Centre (2015/16/T/NZ5/ 00168). F.C.H. was supported by a fellowship from INSERM and acknowledges the members of the GENIUS group (GENetically ImmUne mediated enteropathieS) from ESPGHAN (European Society for Paediatric Gastroenterology, Hepatology and Nutrition), www.genius-group.org. Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = sep,

doi = "10.1038/s41385-021-00423-5",

language = "English",

volume = "14",

pages = "1172--1182",

journal = "Mucosal Immunology",

issn = "1933-0219",

publisher = "Nature Publishing Group",

number = "5",

}

Joosse, ME, Charbit-Henrion, F, Boisgard, R, Raatgeep, R, Lindenbergh-Kortleve, DJ, Costes, LMM, Nugteren, S, Guegan, N, Parlato, M, Veenbergen, S, Malan, V, Nowak, JK, Hollink, IHIM, Mearin, ML, Escher, JC, Cerf-Bensussan, N & Samsom, JN 2021, 'Duplication of the IL2RA locus causes excessive IL-2 signaling and may predispose to very early onset colitis', Mucosal Immunology, vol. 14, no. 5, pp. 1172-1182. https://doi.org/10.1038/s41385-021-00423-5

TY - JOUR

T1 - Duplication of the IL2RA locus causes excessive IL-2 signaling and may predispose to very early onset colitis

AU - Joosse, Maria E.

AU - Charbit-Henrion, Fabienne

AU - Boisgard, Remy

AU - Raatgeep, Rolien (H ).C.

AU - Lindenbergh-Kortleve, Dicky J.

AU - Costes, Léa M.M.

AU - Nugteren, Sandrine

AU - Guegan, Nicolas

AU - Parlato, Marianna

AU - Veenbergen, Sharon

AU - Malan, Valérie

AU - Nowak, Jan K.

AU - Hollink, Iris H.I.M.

AU - Mearin, M. Luisa

AU - Escher, Johanna C.

AU - Cerf-Bensussan, Nadine

AU - Samsom, Janneke N.

N1 - Funding Information: The authors declare no competing financial interests. This work was supported by ERC-2013-AdG-339407-IMMUNOBIOTA and Inserm grant n°ANR-10-LABX-62-IBEID to N.C.B. M.J. was supported by the Netherlands Organization for Scientific Research grant 2013/09420/BOO. L.M.M.C. was funded by SSWO grants (SSWO 608, S16-23) and a research fellowship from the Dutch Sophia Research Foundation. S.V. was funded by the Dutch Sophia Research Foundation SSWO grant (S14-17). J.K.N. was supported by a grant from the Polish National Science Centre (2015/16/T/NZ5/ 00168). F.C.H. was supported by a fellowship from INSERM and acknowledges the members of the GENIUS group (GENetically ImmUne mediated enteropathieS) from ESPGHAN (European Society for Paediatric Gastroenterology, Hepatology and Nutrition), www.genius-group.org. Publisher Copyright: © 2021, The Author(s).

PY - 2021/9

Y1 - 2021/9

N2 - Single genetic mutations predispose to very early onset inflammatory bowel disease (VEO-IBD). Here, we identify a de novo duplication of the 10p15.1 chromosomal region, including the IL2RA locus, in a 2-year-old girl with treatment-resistant pancolitis that was brought into remission by colectomy. Strikingly, after colectomy while the patient was in clinical remission and without medication, the peripheral blood CD4:CD8 ratio was constitutively high and CD25 expression was increased on circulating effector memory, Foxp3+, and Foxp3neg CD4+ T cells compared to healthy controls. This high CD25 expression increased IL-2 signaling, potentiating CD4+ T-cell-derived IFNγ secretion after T-cell receptor (TCR) stimulation. Restoring CD25 expression using the JAK1/3-inhibitor tofacitinib controlled TCR-induced IFNγ secretion in vitro. As diseased colonic tissue, but not the unaffected duodenum, contained mainly CD4+ T cells with a prominent IFNγ-signature, we hypothesize that local microbial stimulation may have initiated colonic disease. Overall, we identify that duplication of the IL2RA locus can associate with VEO-IBD and suggest that increased IL-2 signaling predisposes to colonic intestinal inflammation.

AB - Single genetic mutations predispose to very early onset inflammatory bowel disease (VEO-IBD). Here, we identify a de novo duplication of the 10p15.1 chromosomal region, including the IL2RA locus, in a 2-year-old girl with treatment-resistant pancolitis that was brought into remission by colectomy. Strikingly, after colectomy while the patient was in clinical remission and without medication, the peripheral blood CD4:CD8 ratio was constitutively high and CD25 expression was increased on circulating effector memory, Foxp3+, and Foxp3neg CD4+ T cells compared to healthy controls. This high CD25 expression increased IL-2 signaling, potentiating CD4+ T-cell-derived IFNγ secretion after T-cell receptor (TCR) stimulation. Restoring CD25 expression using the JAK1/3-inhibitor tofacitinib controlled TCR-induced IFNγ secretion in vitro. As diseased colonic tissue, but not the unaffected duodenum, contained mainly CD4+ T cells with a prominent IFNγ-signature, we hypothesize that local microbial stimulation may have initiated colonic disease. Overall, we identify that duplication of the IL2RA locus can associate with VEO-IBD and suggest that increased IL-2 signaling predisposes to colonic intestinal inflammation.

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U2 - 10.1038/s41385-021-00423-5

DO - 10.1038/s41385-021-00423-5

M3 - Article

C2 - 34226674

AN - SCOPUS:85109963968

SN - 1933-0219

VL - 14

SP - 1172

EP - 1182

JO - Mucosal Immunology

JF - Mucosal Immunology

IS - 5

ER -

Duplication of the IL2RA locus causes excessive IL-2 signaling and may predispose to very early onset colitis

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