DECTIN-1: A modifier protein in CTLA-4 haploinsufficiency

Cynthia Turnbull; Josiah Bones; Maurice Stanley; Arti Medhavy; Hao Wang; Ayla May D. Lorenzo; Jean Cappello; Somasundhari Shanmuganandam; Abhimanu Pandey; Sandali Seneviratne; Grant J. Brown; Xiangpeng Meng; David Fulcher; Gaetan Burgio; Si Ming Man; Carmen de Lucas Collantes; Mercedes Gasior; Eduardo López Granados; Pilar Martin; Simon H. Jiang; Matthew C. Cook; Julia I. Ellyard; Vicki Athanasopoulos; Ben Corry; Pablo F. Canete; Carola G. Vinuesa

doi:10.1126/sciadv.adi9566

DECTIN-1: A modifier protein in CTLA-4 haploinsufficiency

Cynthia Turnbull, Josiah Bones, Maurice Stanley, Arti Medhavy, Hao Wang, Ayla May D. Lorenzo, Jean Cappello, Somasundhari Shanmuganandam, Abhimanu Pandey, Sandali Seneviratne, Grant J. Brown, Xiangpeng Meng, David Fulcher, Gaetan Burgio, Si Ming Man, Carmen de Lucas Collantes, Mercedes Gasior, Eduardo López Granados, Pilar Martin, Simon H. JiangMatthew C. Cook, Julia I. Ellyard, Vicki Athanasopoulos, Ben Corry, Pablo F. Canete^*, Carola G. Vinuesa^*

^*Corresponding author for this work

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

5 Citations (Scopus)

Abstract

Autosomal dominant loss-of-function (LoF) variants in cytotoxic T-lymphocyte associated protein 4 (CTLA4) cause immune dysregulation with autoimmunity, immunodeficiency and lymphoproliferation (IDAIL). Incomplete penetrance and variable expressivity are characteristic of IDAIL caused by CTLA-4 haploinsufficiency (CTLA-4h), pointing to a role for genetic modifiers. Here, we describe an IDAIL proband carrying a maternally inherited pathogenic CTLA4 variant and a paternally inherited rare LoF missense variant in CLEC7A, which encodes for the β-glucan pattern recognition receptor DECTIN-1. The CLEC7A variant led to a loss of DECTIN-1 dimerization and surface expression. Notably, DECTIN-1 stimulation promoted human and mouse regulatory T cell (T_reg) differentiation from naïve αβ and γδ T cells, even in the absence of transforming growth factor–β. Consistent with DECTIN-1’s T_reg-boosting ability, partial DECTIN-1 deficiency exacerbated the T_reg defect conferred by CTL4-4h. DECTIN-1/CLEC7A emerges as a modifier gene in CTLA-4h, increasing expressivity of CTLA4 variants and acting in functional epistasis with CTLA-4 to maintain immune homeostasis and tolerance.

Original language	English
Article number	eadi9566
Journal	Science advances
Volume	9
Issue number	49
DOIs	https://doi.org/10.1126/sciadv.adi9566
Publication status	Published - Dec 2023

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Turnbull, C., Bones, J., Stanley, M., Medhavy, A., Wang, H., Lorenzo, A. M. D., Cappello, J., Shanmuganandam, S., Pandey, A., Seneviratne, S., Brown, G. J., Meng, X., Fulcher, D., Burgio, G., Man, S. M., de Lucas Collantes, C., Gasior, M., Granados, E. L., Martin, P., ... Vinuesa, C. G. (2023). DECTIN-1: A modifier protein in CTLA-4 haploinsufficiency. Science advances, 9(49), Article eadi9566. https://doi.org/10.1126/sciadv.adi9566

@article{45e12031ff1c4024bd03e474af5455ee,

title = "DECTIN-1: A modifier protein in CTLA-4 haploinsufficiency",

abstract = "Autosomal dominant loss-of-function (LoF) variants in cytotoxic T-lymphocyte associated protein 4 (CTLA4) cause immune dysregulation with autoimmunity, immunodeficiency and lymphoproliferation (IDAIL). Incomplete penetrance and variable expressivity are characteristic of IDAIL caused by CTLA-4 haploinsufficiency (CTLA-4h), pointing to a role for genetic modifiers. Here, we describe an IDAIL proband carrying a maternally inherited pathogenic CTLA4 variant and a paternally inherited rare LoF missense variant in CLEC7A, which encodes for the β-glucan pattern recognition receptor DECTIN-1. The CLEC7A variant led to a loss of DECTIN-1 dimerization and surface expression. Notably, DECTIN-1 stimulation promoted human and mouse regulatory T cell (Treg) differentiation from na{\"i}ve αβ and γδ T cells, even in the absence of transforming growth factor–β. Consistent with DECTIN-1{\textquoteright}s Treg-boosting ability, partial DECTIN-1 deficiency exacerbated the Treg defect conferred by CTL4-4h. DECTIN-1/CLEC7A emerges as a modifier gene in CTLA-4h, increasing expressivity of CTLA4 variants and acting in functional epistasis with CTLA-4 to maintain immune homeostasis and tolerance.",

author = "Cynthia Turnbull and Josiah Bones and Maurice Stanley and Arti Medhavy and Hao Wang and Lorenzo, {Ayla May D.} and Jean Cappello and Somasundhari Shanmuganandam and Abhimanu Pandey and Sandali Seneviratne and Brown, {Grant J.} and Xiangpeng Meng and David Fulcher and Gaetan Burgio and Man, {Si Ming} and {de Lucas Collantes}, Carmen and Mercedes Gasior and Granados, {Eduardo L{\'o}pez} and Pilar Martin and Jiang, {Simon H.} and Cook, {Matthew C.} and Ellyard, {Julia I.} and Vicki Athanasopoulos and Ben Corry and Canete, {Pablo F.} and Vinuesa, {Carola G.}",

year = "2023",

month = dec,

doi = "10.1126/sciadv.adi9566",

language = "English",

volume = "9",

journal = "Science advances",

issn = "2375-2548",

publisher = "American Association for the Advancement of Science",

number = "49",

}

Turnbull, C, Bones, J, Stanley, M, Medhavy, A, Wang, H, Lorenzo, AMD, Cappello, J, Shanmuganandam, S, Pandey, A , Seneviratne, S, Brown, GJ, Meng, X, Fulcher, D, Burgio, G , Man, SM, de Lucas Collantes, C, Gasior, M, Granados, EL, Martin, P, Jiang, SH, Cook, MC, Ellyard, JI , Athanasopoulos, V , Corry, B, Canete, PF & Vinuesa, CG 2023, 'DECTIN-1: A modifier protein in CTLA-4 haploinsufficiency', Science advances, vol. 9, no. 49, eadi9566. https://doi.org/10.1126/sciadv.adi9566

TY - JOUR

T1 - DECTIN-1

T2 - A modifier protein in CTLA-4 haploinsufficiency

AU - Turnbull, Cynthia

AU - Bones, Josiah

AU - Stanley, Maurice

AU - Medhavy, Arti

AU - Wang, Hao

AU - Lorenzo, Ayla May D.

AU - Cappello, Jean

AU - Shanmuganandam, Somasundhari

AU - Pandey, Abhimanu

AU - Seneviratne, Sandali

AU - Brown, Grant J.

AU - Meng, Xiangpeng

AU - Fulcher, David

AU - Burgio, Gaetan

AU - Man, Si Ming

AU - de Lucas Collantes, Carmen

AU - Gasior, Mercedes

AU - Granados, Eduardo López

AU - Martin, Pilar

AU - Jiang, Simon H.

AU - Cook, Matthew C.

AU - Ellyard, Julia I.

AU - Athanasopoulos, Vicki

AU - Corry, Ben

AU - Canete, Pablo F.

AU - Vinuesa, Carola G.

PY - 2023/12

Y1 - 2023/12

N2 - Autosomal dominant loss-of-function (LoF) variants in cytotoxic T-lymphocyte associated protein 4 (CTLA4) cause immune dysregulation with autoimmunity, immunodeficiency and lymphoproliferation (IDAIL). Incomplete penetrance and variable expressivity are characteristic of IDAIL caused by CTLA-4 haploinsufficiency (CTLA-4h), pointing to a role for genetic modifiers. Here, we describe an IDAIL proband carrying a maternally inherited pathogenic CTLA4 variant and a paternally inherited rare LoF missense variant in CLEC7A, which encodes for the β-glucan pattern recognition receptor DECTIN-1. The CLEC7A variant led to a loss of DECTIN-1 dimerization and surface expression. Notably, DECTIN-1 stimulation promoted human and mouse regulatory T cell (Treg) differentiation from naïve αβ and γδ T cells, even in the absence of transforming growth factor–β. Consistent with DECTIN-1’s Treg-boosting ability, partial DECTIN-1 deficiency exacerbated the Treg defect conferred by CTL4-4h. DECTIN-1/CLEC7A emerges as a modifier gene in CTLA-4h, increasing expressivity of CTLA4 variants and acting in functional epistasis with CTLA-4 to maintain immune homeostasis and tolerance.

AB - Autosomal dominant loss-of-function (LoF) variants in cytotoxic T-lymphocyte associated protein 4 (CTLA4) cause immune dysregulation with autoimmunity, immunodeficiency and lymphoproliferation (IDAIL). Incomplete penetrance and variable expressivity are characteristic of IDAIL caused by CTLA-4 haploinsufficiency (CTLA-4h), pointing to a role for genetic modifiers. Here, we describe an IDAIL proband carrying a maternally inherited pathogenic CTLA4 variant and a paternally inherited rare LoF missense variant in CLEC7A, which encodes for the β-glucan pattern recognition receptor DECTIN-1. The CLEC7A variant led to a loss of DECTIN-1 dimerization and surface expression. Notably, DECTIN-1 stimulation promoted human and mouse regulatory T cell (Treg) differentiation from naïve αβ and γδ T cells, even in the absence of transforming growth factor–β. Consistent with DECTIN-1’s Treg-boosting ability, partial DECTIN-1 deficiency exacerbated the Treg defect conferred by CTL4-4h. DECTIN-1/CLEC7A emerges as a modifier gene in CTLA-4h, increasing expressivity of CTLA4 variants and acting in functional epistasis with CTLA-4 to maintain immune homeostasis and tolerance.

UR - http://www.scopus.com/inward/record.url?scp=85179019170&partnerID=8YFLogxK

U2 - 10.1126/sciadv.adi9566

DO - 10.1126/sciadv.adi9566

M3 - Article

SN - 2375-2548

VL - 9

JO - Science advances

JF - Science advances

IS - 49

M1 - eadi9566

ER -

DECTIN-1: A modifier protein in CTLA-4 haploinsufficiency

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