Human RHOH deficiency causes T cell defects and susceptibility to EV-HPV infections
Amandine Crequer
(1, 2)
,
Anja Troeger
(3, 4)
,
Etienne Patin
(5)
,
Cindy Ma
(6)
,
Capucine Picard
(7, 8)
,
Vincent Pedergnana
(7)
,
Claire Fieschi
(9, 10)
,
Annick Lim
(11)
,
Avinash Abhyankar
(1)
,
Laure Gineau
(7)
,
Ingrid Mueller-Fleckenstein
(12)
,
Monika Schmidt
(12)
,
Alain Taieb
(13, 14)
,
James Krueger
(15)
,
Laurent Abel
(1, 7)
,
Stuart Tangye
(6)
,
Gérard Orth
(11)
,
David Williams
(3, 4)
,
Jean-Laurent Casanova
(1, 7, 8)
,
Emmanuelle Jouanguy
(1, 7)
1
St. Giles Laboratory of Human Genetics of Infectious Diseases
2 UPD5 - Université Paris Descartes - Paris 5
3 Boston Children's Hospital
4 Dana-Farber Cancer Institute [Boston]
5 Génétique Evolutive Humaine - Human Evolutionary Genetics
6 UNSW - University of New South Wales [Sydney]
7 Inserm U980 - Génétique Humaine des Maladies Infectieuses
8 Hôpital Necker - Enfants Malades [AP-HP]
9 Service d'Immunopathologie [Hôpital Saint-Louis, Paris]
10 Différenciation des cellules B, hémopathies, lymphoïdes et déficit de l'immunité humorale
11 IP - Institut Pasteur [Paris]
12 FAU - Friedrich-Alexander Universität Erlangen-Nürnberg = University of Erlangen-Nuremberg
13 Biothérapies des maladies génétiques et cancers
14 CHU Bordeaux
15 Rockefeller University [New York]
2 UPD5 - Université Paris Descartes - Paris 5
3 Boston Children's Hospital
4 Dana-Farber Cancer Institute [Boston]
5 Génétique Evolutive Humaine - Human Evolutionary Genetics
6 UNSW - University of New South Wales [Sydney]
7 Inserm U980 - Génétique Humaine des Maladies Infectieuses
8 Hôpital Necker - Enfants Malades [AP-HP]
9 Service d'Immunopathologie [Hôpital Saint-Louis, Paris]
10 Différenciation des cellules B, hémopathies, lymphoïdes et déficit de l'immunité humorale
11 IP - Institut Pasteur [Paris]
12 FAU - Friedrich-Alexander Universität Erlangen-Nürnberg = University of Erlangen-Nuremberg
13 Biothérapies des maladies génétiques et cancers
14 CHU Bordeaux
15 Rockefeller University [New York]
Etienne Patin
- Fonction : Auteur
- PersonId : 179015
- IdHAL : etienne-patin
- ORCID : 0000-0002-9911-4459
- IdRef : 132614553
Cindy Ma
- Fonction : Auteur
- PersonId : 794453
- ORCID : 0000-0001-5387-8413
Capucine Picard
- Fonction : Auteur
- PersonId : 758297
- ORCID : 0000-0001-8788-5056
- IdRef : 091572363
Vincent Pedergnana
- Fonction : Auteur
- PersonId : 174866
- IdHAL : vincent-pedergnana
- ORCID : 0000-0002-7852-5339
- IdRef : 175475547
Monika Schmidt
- Fonction : Auteur
- PersonId : 779072
- ORCID : 0000-0003-4984-9155
Laurent Abel
- Fonction : Auteur
- PersonId : 756191
- ORCID : 0000-0001-7016-6493
- IdRef : 07779432X
Stuart Tangye
- Fonction : Auteur
- PersonId : 804753
- ORCID : 0000-0002-5360-5180
David Williams
- Fonction : Auteur
- PersonId : 775424
- ORCID : 0000-0003-4033-0867
Jean-Laurent Casanova
- Fonction : Auteur
- PersonId : 756193
- ORCID : 0000-0002-7782-4169
- IdRef : 073388726
Emmanuelle Jouanguy
- Fonction : Auteur
- PersonId : 756190
- ORCID : 0000-0002-7358-9157
- IdRef : 224367455
Résumé
Epidermodysplasia verruciformis (EV) is a rare genetic disorder characterized by increased susceptibility to specific human papillomaviruses, the betapapillomaviruses. These EV-HPVs cause warts and increase the risk of skin carcinomas in otherwise healthy individuals. Inactivating mutations in epidermodysplasia verruciformis 1 (EVER1) or EVER2 have been identified in most, but not all, patients with autosomal recessive EV. We found that 2 young adult siblings presenting with T cell deficiency and various infectious diseases, including persistent EV-HPV infections, were homozygous for a mutation creating a stop codon in the ras homolog gene family member H (RHOH) gene. RHOH encodes an atypical Rho GTPase expressed predominantly in hematopoietic cells. Patients' circulating T cells contained predominantly effector memory T cells, which displayed impaired TCR signaling. Additionally, very few circulating T cells expressed the β7 integrin subunit, which homes T cells to specific tissues. Similarly, Rhoh-null mice exhibited a severe overall T cell defect and abnormally small numbers of circulating β7-positive cells. Expression of the WT, but not of the mutated RHOH, allele in Rhoh-/- hematopoietic stem cells corrected the T cell lymphopenia in mice after bone marrow transplantation. We conclude that RHOH deficiency leads to T cell defects and persistent EV-HPV infections, suggesting that T cells play a role in the pathogenesis of chronic EV-HPV infections.