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Humans with inherited T cell CD28 deficiency are susceptible to skin papillomaviruses but are otherwise healthy.

ABSTRACT: We study a patient with the human papilloma virus (HPV)-2-driven "tree-man" phenotype and two relatives with unusually severe HPV4-driven warts. The giant horns form an HPV-2-driven multifocal benign epithelial tumor overexpressing viral oncogenes in the epidermis basal layer. The patients are unexpectedly homozygous for a private CD28 variant. They have no detectable CD28 on their T cells, with the exception of a small contingent of revertant memory CD4⁺ T cells. T cell development is barely affected, and T cells respond to CD3 and CD2, but not CD28, costimulation. Although the patients do not display HPV-2- and HPV-4-reactive CD4⁺ T cells in vitro, they make antibodies specific for both viruses in vivo. CD28-deficient mice are susceptible to cutaneous infections with the mouse papillomavirus MmuPV1. The control of HPV-2 and HPV-4 in keratinocytes is dependent on the T cell CD28 co-activation pathway. Surprisingly, human CD28-dependent T cell responses are largely redundant for protective immunity.

SUBMITTER: Beziat V

PROVIDER: S-EPMC8329841 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Humans with inherited T cell CD28 deficiency are susceptible to skin papillomaviruses but are otherwise healthy.

Béziat Vivien V Rapaport Franck F Hu Jiafen J Titeux Matthias M Bonnet des Claustres Mathilde M Bourgey Mathieu M Griffin Heather H Bandet Élise É Ma Cindy S CS Sherkat Roya R Rokni-Zadeh Hassan H Louis David M DM Changi-Ashtiani Majid M Delmonte Ottavia M OM Fukushima Toshiaki T Habib Tanwir T Guennoun Andrea A Khan Taushif T Bender Noemi N Rahman Mahbuba M About Frédégonde F Yang Rui R Rao Geetha G Rouzaud Claire C Li Jingwei J Shearer Debra D Balogh Karla K Al Ali Fatima F Ata Manar M Dabiri Soroosh S Momenilandi Mana M Nammour Justine J Alyanakian Marie-Alexandra MA Leruez-Ville Marianne M Guenat David D Materna Marie M Marcot Léa L Vladikine Natasha N Soret Christine C Vahidnezhad Hassan H Youssefian Leila L Saeidian Amir Hossein AH Uitto Jouni J Catherinot Émilie É Navabi Shadi Sadat SS Zarhrate Mohammed M Woodley David T DT Jeljeli Mohamed M Abraham Thomas T Belkaya Serkan S Lorenzo Lazaro L Rosain Jérémie J Bayat Mousa M Lanternier Fanny F Lortholary Olivier O Zakavi Faramarz F Gros Philippe P Orth Gérard G Abel Laurent L Prétet Jean-Luc JL Fraitag Sylvie S Jouanguy Emmanuelle E Davis Mark M MM Tangye Stuart G SG Notarangelo Luigi D LD Marr Nico N Waterboer Tim T Langlais David D Doorbar John J Hovnanian Alain A Christensen Neil N Bossuyt Xavier X Shahrooei Mohammad M Casanova Jean-Laurent JL

Cell 20210701 14

We study a patient with the human papilloma virus (HPV)-2-driven "tree-man" phenotype and two relatives with unusually severe HPV4-driven warts. The giant horns form an HPV-2-driven multifocal benign epithelial tumor overexpressing viral oncogenes in the epidermis basal layer. The patients are unexpectedly homozygous for a private CD28 variant. They have no detectable CD28 on their T cells, with the exception of a small contingent of revertant memory CD4<sup>+</sup> T cells. T cell development i ...[more]

PMID: 34214472

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Project description:BACKGROUND:Invasive infections of the central nervous system (CNS) or digestive tract caused by commensal fungi of the genus Candida are rare and life-threatening. The known risk factors include acquired and inherited immunodeficiencies, with patients often displaying a history of multiple infections. Cases of meningoencephalitis, colitis, or both caused by Candida species remain unexplained. OBJECTIVE:We studied 5 previously healthy children and adults with unexplained invasive disease of the CNS, digestive tract, or both caused by Candida species. The patients were aged 39, 7, 17, 37, and 26 years at the time of infection and were unrelated, but each was born to consanguineous parents of Turkish (2 patients), Iranian, Moroccan, or Pakistani origin. Meningoencephalitis was reported in 3 patients, meningoencephalitis associated with colitis was reported in a fourth patient, and the fifth patient had colitis only. METHODS:Inherited caspase recruitment domain family, member 9 (CARD9) deficiency was recently reported in otherwise healthy patients with other forms of severe disease caused by Candida, Trichophyton, Phialophora, and Exophiala species, including meningoencephalitis but not colitis caused by Candida and Exophiala species. Therefore we sequenced CARD9 in the 5 patients. RESULTS:All patients were found to be homozygous for rare and deleterious mutant CARD9 alleles: R70W and Q289* for the 3 patients with Candida albicans-induced meningoencephalitis, R35Q for the patient with meningoencephalitis and colitis caused by Candida glabrata, and Q295* for the patient with Candida albicans-induced colitis. Regardless of their levels of mutant CARD9 protein, the patients' monocyte-derived dendritic cells responded poorly to CARD9-dependent fungal agonists (curdlan, heat-killed C albicans, Saccharomyces cerevisiae, and Exophiala dermatitidis). CONCLUSION:Invasive infections of the CNS or digestive tract caused by Candida species in previously healthy children and even adults might be caused by inherited CARD9 deficiency.

Dataset Information

Humans with inherited T cell CD28 deficiency are susceptible to skin papillomaviruses but are otherwise healthy.

Publications

Humans with inherited T cell CD28 deficiency are susceptible to skin papillomaviruses but are otherwise healthy.

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