Human RHOH deficiency causes T cell defects and susceptibility to EV-HPV infections
Amandine Crequer, Anja Troeger, Etienne Patin, Cindy S. Ma, Capucine Picard, Vincent Pedergnana, Claire Fieschi, Annick Lim, Avinash Abhyankar, Laure Gineau, Ingrid Mueller-Fleckenstein, Monika Schmidt, Alain Taieb, James Krueger, Laurent Abel, Stuart G. Tangye, Gérard Orth, David A. Williams, Jean-Laurent Casanova, Emmanuelle Jouanguy
Amandine Crequer, Anja Troeger, Etienne Patin, Cindy S. Ma, Capucine Picard, Vincent Pedergnana, Claire Fieschi, Annick Lim, Avinash Abhyankar, Laure Gineau, Ingrid Mueller-Fleckenstein, Monika Schmidt, Alain Taieb, James Krueger, Laurent Abel, Stuart G. Tangye, Gérard Orth, David A. Williams, Jean-Laurent Casanova, Emmanuelle Jouanguy
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Research Article Immunology

Human RHOH deficiency causes T cell defects and susceptibility to EV-HPV infections

Abstract

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.

Authors

Amandine Crequer, Anja Troeger, Etienne Patin, Cindy S. Ma, Capucine Picard, Vincent Pedergnana, Claire Fieschi, Annick Lim, Avinash Abhyankar, Laure Gineau, Ingrid Mueller-Fleckenstein, Monika Schmidt, Alain Taieb, James Krueger, Laurent Abel, Stuart G. Tangye, Gérard Orth, David A. Williams, Jean-Laurent Casanova, Emmanuelle Jouanguy

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Figure 2

The Y38X RHOH allele is loss of function in the mouse model and is associated with an impaired phosphorylation of ZAP70 upon TCR stimulation in the patients’ saimiri T cells.

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The Y38X RHOH allele is loss of function in the mouse model and is assoc...
(A) Bone marrow cells from Rhoh–/– mice (KO) of mixed background were transduced with an empty retroviral vector encoding YFP or a retroviral vector coexpressing the YFP gene and WT RHOH, Y38X RHOH, or 139-C RHOH genes and transplanted into sublethally irradiated Rag2–/– recipient mice. Normal bone marrow cells transduced with an empty vector were included as a control. The percentage of CD3+ cells within the YFP+-transduced T cell group was assessed in the blood of recipient mice 3 months after transplantation by flow cytometry (mean ± SEM, n = 4 recipients per construct). *P < 0.05; **P < 0.005. (B) Representative immunoblots of cell lysates extracted from saimiri T cells of a healthy control and the 2 patients (P1 and P2) following OKT3 stimulation, probed with anti-ZAP70 and anti–phospho-ZAP70 antibodies. β-Actin was used as an additional protein-loading control. (C) Representative immunoblot analysis of cell lysates extracted from YPF+ sorted saimiri T cells (control and patient P2) transduced with a vector encoding YFP and the HA-tagged mutant Y38X RHOH (HA-Y38X), YFP and the HA-tagged WT RHOH (HA-WT), or YFP alone (MOCK), subsequently stimulated with OKT3. Lysates were blotted with anti-ZAP70 and anti-phospho-ZAP70 antibodies. β-Actin was used as an additional protein-loading control.