Impairment of immunity to Candida and Mycobacterium in humans with bi-allelic RORC mutations

Satoshi Okada, Janet G. Markle, Elissa K. Deenick, Federico Mele, Dina Averbuch, Macarena Lagos, Mohammed Alzahrani, Saleh Al-Muhsen, Rabih Halwani, Cindy S. Ma, Natalie Wong, Claire Soudais, Lauren A. Henderson, Hiyam Marzouqa, Jamal Shamma, Marcela Gonzalez, Rubén Martinez-Barricarte, Chizuru Okada, Danielle T. Avery, Daniela LatorreCaroline Deswarte, Fabienne Jabot-Hanin, Egidio Torrado, Jeffrey Fountain, Abdelaziz Belkadi, Yuval Itan, Bertrand Boisson, Mélanie Migaud, Cecilia S. Lindestam Arlehamn, Alessandro Sette, Sylvain Breton, James Cluskey, Jamie Rossjohn, Jean Pierre De Villartay, Despina Moshous, Sophie Hambleton, Sylvain Latour, Peter D. Arkwright, Capucine Picard, Olivier Lantz, Dan Engelhard, Masao Kobayashi, Laurent Abel, Andrea M. Cooper, Luigi D. Notarangelo, Stéphanie Boisson-Dupuis, Anne Puel, Federica Sallusto, Jacinta Bustamante, Stuart G. Tangye, Jean Laurent Casanova

Research output: Contribution to journalArticle

159 Citations (Scopus)

Abstract

Human inborn errors of immunity mediated by the cytokines interleukin-17A and interleukin-17F (IL-17A/F) underlie mucocutaneous candidiasis, whereas inborn errors of interferon-γ (IFN-γ) immunity underlie mycobacterial disease. We report the discovery of bi-allelic RORC loss-of-function mutations in seven individuals from three kindreds of different ethnic origins with both candidiasis and mycobacteriosis. The lack of functional RORγ and RORγT isoforms resulted in the absence of IL-17A/F-producing T cells in these individuals, probably accounting for their chronic candidiasis. Unexpectedly, leukocytes from RORγ- and RORγT-deficient individuals also displayed an impaired IFN-γ response to Mycobacterium. This principally reflected profoundly defective IFN-γ production by circulating γδ T cells and CD4+CCR6+CXCR3+ αβ T cells. In humans, both mucocutaneous immunity to Candida and systemic immunity to Mycobacterium require RORγ, RORγT, or both.

Original languageEnglish
Pages (from-to)606-613
Number of pages8
JournalScience
Volume349
Issue number6248
DOIs
Publication statusPublished - 7 Aug 2015
Externally publishedYes

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Interleukin-17
Mycobacterium
Candida
Candidiasis
Immunity
Interferons
Mutation
T-Lymphocytes
Loss of Heterozygosity
Protein Isoforms
Leukocytes
Cytokines

ASJC Scopus subject areas

  • General

Cite this

Okada, S., Markle, J. G., Deenick, E. K., Mele, F., Averbuch, D., Lagos, M., ... Casanova, J. L. (2015). Impairment of immunity to Candida and Mycobacterium in humans with bi-allelic RORC mutations. Science, 349(6248), 606-613. https://doi.org/10.1126/science.aaa4282

Impairment of immunity to Candida and Mycobacterium in humans with bi-allelic RORC mutations. / Okada, Satoshi; Markle, Janet G.; Deenick, Elissa K.; Mele, Federico; Averbuch, Dina; Lagos, Macarena; Alzahrani, Mohammed; Al-Muhsen, Saleh; Halwani, Rabih; Ma, Cindy S.; Wong, Natalie; Soudais, Claire; Henderson, Lauren A.; Marzouqa, Hiyam; Shamma, Jamal; Gonzalez, Marcela; Martinez-Barricarte, Rubén; Okada, Chizuru; Avery, Danielle T.; Latorre, Daniela; Deswarte, Caroline; Jabot-Hanin, Fabienne; Torrado, Egidio; Fountain, Jeffrey; Belkadi, Abdelaziz; Itan, Yuval; Boisson, Bertrand; Migaud, Mélanie; Lindestam Arlehamn, Cecilia S.; Sette, Alessandro; Breton, Sylvain; Cluskey, James; Rossjohn, Jamie; De Villartay, Jean Pierre; Moshous, Despina; Hambleton, Sophie; Latour, Sylvain; Arkwright, Peter D.; Picard, Capucine; Lantz, Olivier; Engelhard, Dan; Kobayashi, Masao; Abel, Laurent; Cooper, Andrea M.; Notarangelo, Luigi D.; Boisson-Dupuis, Stéphanie; Puel, Anne; Sallusto, Federica; Bustamante, Jacinta; Tangye, Stuart G.; Casanova, Jean Laurent.

In: Science, Vol. 349, No. 6248, 07.08.2015, p. 606-613.

Research output: Contribution to journalArticle

Okada, S, Markle, JG, Deenick, EK, Mele, F, Averbuch, D, Lagos, M, Alzahrani, M, Al-Muhsen, S, Halwani, R, Ma, CS, Wong, N, Soudais, C, Henderson, LA, Marzouqa, H, Shamma, J, Gonzalez, M, Martinez-Barricarte, R, Okada, C, Avery, DT, Latorre, D, Deswarte, C, Jabot-Hanin, F, Torrado, E, Fountain, J, Belkadi, A, Itan, Y, Boisson, B, Migaud, M, Lindestam Arlehamn, CS, Sette, A, Breton, S, Cluskey, J, Rossjohn, J, De Villartay, JP, Moshous, D, Hambleton, S, Latour, S, Arkwright, PD, Picard, C, Lantz, O, Engelhard, D, Kobayashi, M, Abel, L, Cooper, AM, Notarangelo, LD, Boisson-Dupuis, S, Puel, A, Sallusto, F, Bustamante, J, Tangye, SG & Casanova, JL 2015, 'Impairment of immunity to Candida and Mycobacterium in humans with bi-allelic RORC mutations', Science, vol. 349, no. 6248, pp. 606-613. https://doi.org/10.1126/science.aaa4282
Okada S, Markle JG, Deenick EK, Mele F, Averbuch D, Lagos M et al. Impairment of immunity to Candida and Mycobacterium in humans with bi-allelic RORC mutations. Science. 2015 Aug 7;349(6248):606-613. https://doi.org/10.1126/science.aaa4282
Okada, Satoshi ; Markle, Janet G. ; Deenick, Elissa K. ; Mele, Federico ; Averbuch, Dina ; Lagos, Macarena ; Alzahrani, Mohammed ; Al-Muhsen, Saleh ; Halwani, Rabih ; Ma, Cindy S. ; Wong, Natalie ; Soudais, Claire ; Henderson, Lauren A. ; Marzouqa, Hiyam ; Shamma, Jamal ; Gonzalez, Marcela ; Martinez-Barricarte, Rubén ; Okada, Chizuru ; Avery, Danielle T. ; Latorre, Daniela ; Deswarte, Caroline ; Jabot-Hanin, Fabienne ; Torrado, Egidio ; Fountain, Jeffrey ; Belkadi, Abdelaziz ; Itan, Yuval ; Boisson, Bertrand ; Migaud, Mélanie ; Lindestam Arlehamn, Cecilia S. ; Sette, Alessandro ; Breton, Sylvain ; Cluskey, James ; Rossjohn, Jamie ; De Villartay, Jean Pierre ; Moshous, Despina ; Hambleton, Sophie ; Latour, Sylvain ; Arkwright, Peter D. ; Picard, Capucine ; Lantz, Olivier ; Engelhard, Dan ; Kobayashi, Masao ; Abel, Laurent ; Cooper, Andrea M. ; Notarangelo, Luigi D. ; Boisson-Dupuis, Stéphanie ; Puel, Anne ; Sallusto, Federica ; Bustamante, Jacinta ; Tangye, Stuart G. ; Casanova, Jean Laurent. / Impairment of immunity to Candida and Mycobacterium in humans with bi-allelic RORC mutations. In: Science. 2015 ; Vol. 349, No. 6248. pp. 606-613.
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abstract = "Human inborn errors of immunity mediated by the cytokines interleukin-17A and interleukin-17F (IL-17A/F) underlie mucocutaneous candidiasis, whereas inborn errors of interferon-γ (IFN-γ) immunity underlie mycobacterial disease. We report the discovery of bi-allelic RORC loss-of-function mutations in seven individuals from three kindreds of different ethnic origins with both candidiasis and mycobacteriosis. The lack of functional RORγ and RORγT isoforms resulted in the absence of IL-17A/F-producing T cells in these individuals, probably accounting for their chronic candidiasis. Unexpectedly, leukocytes from RORγ- and RORγT-deficient individuals also displayed an impaired IFN-γ response to Mycobacterium. This principally reflected profoundly defective IFN-γ production by circulating γδ T cells and CD4+CCR6+CXCR3+ αβ T cells. In humans, both mucocutaneous immunity to Candida and systemic immunity to Mycobacterium require RORγ, RORγT, or both.",
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AU - Mele, Federico

AU - Averbuch, Dina

AU - Lagos, Macarena

AU - Alzahrani, Mohammed

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AU - Jabot-Hanin, Fabienne

AU - Torrado, Egidio

AU - Fountain, Jeffrey

AU - Belkadi, Abdelaziz

AU - Itan, Yuval

AU - Boisson, Bertrand

AU - Migaud, Mélanie

AU - Lindestam Arlehamn, Cecilia S.

AU - Sette, Alessandro

AU - Breton, Sylvain

AU - Cluskey, James

AU - Rossjohn, Jamie

AU - De Villartay, Jean Pierre

AU - Moshous, Despina

AU - Hambleton, Sophie

AU - Latour, Sylvain

AU - Arkwright, Peter D.

AU - Picard, Capucine

AU - Lantz, Olivier

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AU - Cooper, Andrea M.

AU - Notarangelo, Luigi D.

AU - Boisson-Dupuis, Stéphanie

AU - Puel, Anne

AU - Sallusto, Federica

AU - Bustamante, Jacinta

AU - Tangye, Stuart G.

AU - Casanova, Jean Laurent

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N2 - Human inborn errors of immunity mediated by the cytokines interleukin-17A and interleukin-17F (IL-17A/F) underlie mucocutaneous candidiasis, whereas inborn errors of interferon-γ (IFN-γ) immunity underlie mycobacterial disease. We report the discovery of bi-allelic RORC loss-of-function mutations in seven individuals from three kindreds of different ethnic origins with both candidiasis and mycobacteriosis. The lack of functional RORγ and RORγT isoforms resulted in the absence of IL-17A/F-producing T cells in these individuals, probably accounting for their chronic candidiasis. Unexpectedly, leukocytes from RORγ- and RORγT-deficient individuals also displayed an impaired IFN-γ response to Mycobacterium. This principally reflected profoundly defective IFN-γ production by circulating γδ T cells and CD4+CCR6+CXCR3+ αβ T cells. In humans, both mucocutaneous immunity to Candida and systemic immunity to Mycobacterium require RORγ, RORγT, or both.

AB - Human inborn errors of immunity mediated by the cytokines interleukin-17A and interleukin-17F (IL-17A/F) underlie mucocutaneous candidiasis, whereas inborn errors of interferon-γ (IFN-γ) immunity underlie mycobacterial disease. We report the discovery of bi-allelic RORC loss-of-function mutations in seven individuals from three kindreds of different ethnic origins with both candidiasis and mycobacteriosis. The lack of functional RORγ and RORγT isoforms resulted in the absence of IL-17A/F-producing T cells in these individuals, probably accounting for their chronic candidiasis. Unexpectedly, leukocytes from RORγ- and RORγT-deficient individuals also displayed an impaired IFN-γ response to Mycobacterium. This principally reflected profoundly defective IFN-γ production by circulating γδ T cells and CD4+CCR6+CXCR3+ αβ T cells. In humans, both mucocutaneous immunity to Candida and systemic immunity to Mycobacterium require RORγ, RORγT, or both.

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