The immunopathological landscape of human pre-TCRα deficiency: From rare to common variants

被引：13

作者：

Materna, Marie ^{[1
,2
]}

Delmonte, Ottavia M. ^{[3
]}

Bosticardo, Marita ^{[3
]}

Momenilandi, Mana ^{[1
,2
]}

Conrey, Peyton E. ^{[4
]}

Charmeteau-De Muylder, Benedicte ^{[5
]}

Bravetti, Clotilde ^{[6
,7
,8
]}

Bellworthy, Rebecca ^{[9
]}

Cederholm, Axel ^{[10
]}

Staels, Frederik ^{[11
]}

Ganoza, Christian A. ^{[12
]}

Darko, Samuel ^{[13
]}

Sayed, Samir ^{[4
]}

Le Floc'h, Corentin ^{[1
,2
]}

Ogishi, Masato ^{[14
]}

Rinchai, Darawan ^{[14
]}

Guenoun, Andrea ^{[15
]}

Bolze, Alexandre ^{[16
]}

Khan, Taushif ^{[15
,17
]}

Gervais, Adrian ^{[1
,2
,3
]}

Krueger, Renate ^{[18
,19
,20
,21
]}

Voeller, Mirjam ^{[18
,19
,20
,21
]}

Palterer, Boaz ^{[3
]}

Sadeghi-Shabestari, Mahnaz ^{[22
]}

de Septenville, Anne Langlois ^{[6
,7
]}

Schramm, Chaim A. ^{[13
]}

Shah, Sanjana ^{[13
]}

Tello-Cajiao, John J. ^{[4
,23
]}

Pala, Francesca ^{[3
]}

Amini, Kayla ^{[3
]}

Campos, Jose S. ^{[4
]}

Lima, Noemia Santana ^{[13
]}

Eriksson, Daniel ^{[24
,25
]}

Levy, Romain ^{[1
,2
,26
]}

Seeleuthner, Yoann ^{[1
,2
]}

Jyonouchi, Soma ^{[4
]}

Ata, Manar ^{[15
]}

Al Ali, Fatima ^{[15
]}

Deswarte, Caroline ^{[1
,2
]}

Pereira, Anais ^{[1
,2
]}

Megret, Jerome ^{[27
]}

Le Voyer, Tom ^{[1
,2
]}

Bastard, Paul ^{[1
,2
,14
,26
]}

Berteloot, Laureline ^{[28
]}

Dussiot, Michael ^{[2
,29
]}

Vladikine, Natasha ^{[1
,2
]}

Cardenas, Paula P. ^{[30
,31
]}

Jouanguy, Emmanuelle ^{[1
,2
,14
]}

Alqahtani, Mashael ^{[32
]}

Hasan, Amal ^{[33
]}

机构：

[1] Necker Hosp Sick Children, Lab Human Genet Infect Dis, Necker Branch, INSERM, Paris, France

[2] Univ Paris Cite, Imagine Inst, Paris, France

[3] NIAID, Lab Clin Immunol & Microbiol, NIH, Bethesda, MD USA

[4] Childrens Hosp Philadelphia, Div Allergy Immunol, Dept Pediat, Philadelphia, PA USA

[5] Univ Paris, CNRS, Inst Cochin, INSERM,U1016,UMR8104, Paris, France

[6] Hop La Pitie Salpetriere, AP HP, Dept Biol Hematol, Paris, France

[7] Sorbonne Univ, Paris, France

[8] Sorbonne Univ, Paris Canc Inst CURAMUS, INSERM, U1138, Paris, France

[9] McGill Univ, Dahdaleh Inst Genom Med, Deptartment Human Genet, Montreal, PQ, Canada

[10] Uppsala Univ, Dept Med Biochem & Microbiol, Sci Life Lab, Uppsala, Sweden

[11] Katholieke Univ Leuven, Dept Microbiol Immunol & Transplantat, Allergy & Clin Immunol Res Grp, Leuven, Belgium

[12] Centogene GmbH, Rostock, Germany

[13] NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD USA

[14] Rockefeller Univ, St Giles Lab Human Genet Infect Dis, Rockefeller Branch, 1230 York Ave, New York, NY 10021 USA

[15] Sidra Med, Dept Human Immunol, Doha, Qatar

[16] Helix, San Mateo, CA USA

[17] Jackson Lab, Farmington, CT USA

[18] Charite Univ Med Berlin, Dept Pediat Resp Med Immunol & Crit Care Med, Berlin, Germany

[19] Free Univ Berlin, Berlin, Germany

[20] Humboldt Univ, Berlin, Germany

[21] Berlin Inst Hlth, Berlin, Germany

[22] Tabriz Univ Med Sci, Immunol Res Ctr, TB & Lung Dis Res Ctr, Mardaniazar Children Hosp, Tabriz, Iran

[23] Childrens Hosp Philadelphia, Dept Pathol, Philadelphia, PA USA

[24] Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden

[25] Univ Hosp, Clin Genet Sect, Uppsala, Sweden

[26] Necker Hosp Sick Children, AP HP, Pediat Immunol Hematol & Rheumatol Unit, Paris, France

[27] CNRS, UAR3633, INSERM, Cytometry Core Facil,SFR Necker,US24, Paris, France

[28] Univ Hosp Necker Enfants Malad, AP HP, Dept Pediat Radiol, Paris, France

[29] INSERM, Lab Mol Mech Hematol Disorders & Therapeut Implic, UMR 1163, Paris, France

[30] Univ Complutense Madrid, Sch Med, Dept Immunol Ophthalmol & ENT, Madrid, Spain

[31] 12 Octubre Hlth Res Inst Imas12, Madrid, Spain

[32] King Faisal Specialist Hosp & Res Ctr, Ctr Genom Med, Dept Translat Genom, Riyadh, Saudi Arabia

[33] Dasman Diabet Inst, Div Res, Dept Translat Res, Kuwait, Kuwait

[34] Dasman Diabet Inst, Div Res, Dept Genet & Bioinformat, Kuwait, Kuwait

[35] Univ Antwerp, Univ Antwerp Hosp, Dept Immunol Allergol & Rheumatol, Antwerp, Belgium

[36] Necker Hosp Sick Children, AP HP, Immunol Lab, Paris, France

[37] Necker Hosp Sick Children, AP HP, Paris, France

[38] Cochin Hosp, AP HP, APHP CUP, Virol, Paris, France

[39] Univ Montreal, CHU St Justine, Dept Pediat, Dept Microbiol Immunol & Infect Dis, Montreal, PQ, Canada

[40] Univ Autonoma Madrid, Immune Syst Dev & Funct Unit, Ctr Biol Mol Severo Ochoa, CSIC, Madrid, Spain

[41] Childrens Hosp Philadelphia, Div Gastroenterol Hepatol & Nutr, Philadelphia, PA USA

[42] Isfahan Univ Med Sci, Cellular Mol & Genet Res Ctr, Esfahan, Iran

[43] Isfahan Univ Med Sci, Sch Med, Dept Genet & Mol Biol, Esfahan, Iran

[44] Ahvaz Jundishapur Univ Med Sci, Childrens Med Ctr Abuzar, Dept Pediat Neurol, Ahvaz, Iran

[45] Ahvaz Jundishapur Univ Med Sci, Golestan Hosp Clin Res Dev Unit, Ahvaz, Iran

[46] Zanjan Univ Med Sci, Sch Med, Dept Med Biotechnol, Zanjan, Iran

[47] Inst Res Fundamental Sci IPM, Sch Math, Tehran, Iran

[48] Isfahan Univ Med Sci, Pediat Inherited Dis Res Ctr, Res Inst Primordial Prevent Noncommunicable Dis, Esfahan, Iran

[49] Shiraz Univ Med Sci, Neonatal Res Ctr, Shiraz, Iran

[50] Univ Tehran Med Sci, Fac Med, Med Genet Poursina St, Dept Genet, Tehran, Iran

来源：

SCIENCE | 2024年 / 383卷 / 6686期

基金：

瑞典研究理事会; 美国国家卫生研究院;

关键词：

T-CELL-RECEPTOR; GAMMA-DELTA; GENE REARRANGEMENT; ALLELIC EXCLUSION; BETA; EXPRESSION; CHAIN; THYMOCYTES; AUTOANTIBODIES; REPERTOIRE;

D O I：

10.1126/science.adh4059

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

We describe humans with rare biallelic loss-of-function PTCRA variants impairing pre-alpha T cell receptor (pre-TCR alpha) expression. Low circulating naive alpha beta T cell counts at birth persisted over time, with normal memory alpha beta and high gamma delta T cell counts. Their TCR alpha repertoire was biased, which suggests that noncanonical thymic differentiation pathways can rescue alpha beta T cell development. Only a minority of these individuals were sick, with infection, lymphoproliferation, and/or autoimmunity. We also report that 1 in 4000 individuals from the Middle East and South Asia are homozygous for a common hypomorphic PTCRA variant. They had normal circulating naive alpha beta T cell counts but high gamma delta T cell counts. Although residual pre-TCR alpha expression drove the differentiation of more alpha beta T cells, autoimmune conditions were more frequent in these patients compared with the general population.

引用

页数：19