Group 3 innate lymphoid cells mediate early protective immunity against tuberculosis

Amanda Ardain, Racquel Domingo-Gonzalez, Shibali Das, Samuel W Kazer, Nicole C Howard, Alveera Singh, Mushtaq Ahmed, Shepherd Nhamoyebonde, Javier Rangel-Moreno, Paul Ogongo, Lan Lu, Duran Ramsuran, Maria de la Luz Garcia-Hernandez, Tyler K Ulland, Matthew Darby, Eugene Park, Farina Karim, Laura Melocchi, Rajhmun Madansein, Kaylesh Jay DullabhMicah Dunlap, Nancy Marin-Agudelo, Takashi Ebihara, Thumbi Ndung'u, Deepak Kaushal, Alexander S Pym, Jay K Kolls, Adrie Steyn, Joaquín Zúñiga, William Horsnell, Wayne M Yokoyama, Alex K Shalek, Henrik N Kløverpris, Marco Colonna, Alasdair Leslie, Shabaana A Khader

Research output: Contribution to journalArticlepeer-review

63 Citations (Scopus)

Abstract

Tuberculosis is the leading cause of death by an infectious disease worldwide1. However, the involvement of innate lymphoid cells (ILCs) in immune responses to infection with Mycobacterium tuberculosis (Mtb) is unknown. Here we show that circulating subsets of ILCs are depleted from the blood of participants with pulmonary tuberculosis and restored upon treatment. Tuberculosis increased accumulation of ILC subsets in the human lung, coinciding with a robust transcriptional response to infection, including a role in orchestrating the recruitment of immune subsets. Using mouse models, we show that group 3 ILCs (ILC3s) accumulated rapidly in Mtb-infected lungs and coincided with the accumulation of alveolar macrophages. Notably, mice that lacked ILC3s exhibited a reduction in the accumulation of early alveolar macrophages and decreased Mtb control. We show that the C-X-C motif chemokine receptor 5 (CXCR5)-C-X-C motif chemokine ligand 13 (CXCL13) axis is involved in Mtb control, as infection upregulates CXCR5 on circulating ILC3s and increases plasma levels of its ligand, CXCL13, in humans. Moreover, interleukin-23-dependent expansion of ILC3s in mice and production of interleukin-17 and interleukin-22 were found to be critical inducers of lung CXCL13, early innate immunity and the formation of protective lymphoid follicles within granulomas. Thus, we demonstrate an early protective role for ILC3s in immunity to Mtb infection.

Original languageEnglish
Pages (from-to)528-532
Number of pages5
JournalNature
Volume570
Early online date5 Jun 2019
DOIs
Publication statusPublished - 27 Jun 2019

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