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 Dullabh; Micah 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

doi:10.1038/s41586-019-1276-2

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

^*Corresponding author for this work

62 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 language	English
Journal	Nature
Volume	570
Issue number	7762
Pages (from-to)	528-532
Number of pages	5
ISSN	0028-0836
DOIs	https://doi.org/10.1038/s41586-019-1276-2
Publication status	Published - 2019

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Ardain, A., Domingo-Gonzalez, R., Das, S., Kazer, S. W., Howard, N. C., Singh, A., Ahmed, M., Nhamoyebonde, S., Rangel-Moreno, J., Ogongo, P., Lu, L., Ramsuran, D., de la Luz Garcia-Hernandez, M., K. Ulland, T., Darby, M., Park, E., Karim, F., Melocchi, L., Madansein, R., ... Khader, S. A. (2019). Group 3 innate lymphoid cells mediate early protective immunity against tuberculosis. Nature, 570(7762), 528-532. https://doi.org/10.1038/s41586-019-1276-2

Ardain, A, Domingo-Gonzalez, R, Das, S, Kazer, SW, Howard, NC, Singh, A, Ahmed, M, Nhamoyebonde, S, Rangel-Moreno, J, Ogongo, P, Lu, L, Ramsuran, D, de la Luz Garcia-Hernandez, M, K. Ulland, T, Darby, M, Park, E, Karim, F, Melocchi, L, Madansein, R, Dullabh, KJ, Dunlap, M, Marin-Agudelo, N, Ebihara, T, Ndung’u, T, Kaushal, D, Pym, AS, Kolls, JK, Steyn, A, Zúñiga, J, Horsnell, W, Yokoyama, WM, Shalek, AK, Kløverpris, HN, Colonna, M, Leslie, A & Khader, SA 2019, 'Group 3 innate lymphoid cells mediate early protective immunity against tuberculosis', Nature, vol. 570, no. 7762, pp. 528-532. https://doi.org/10.1038/s41586-019-1276-2

@article{87d4964da26b4af79a7906af9def5340,

title = "Group 3 innate lymphoid cells mediate early protective immunity against tuberculosis",

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.",

author = "Amanda Ardain and Racquel Domingo-Gonzalez and Shibali Das and Kazer, {Samuel W.} and Howard, {Nicole C.} and Alveera Singh and Mushtaq Ahmed and Shepherd Nhamoyebonde and Javier Rangel-Moreno and Paul Ogongo and Lan Lu and Duran Ramsuran and {de la Luz Garcia-Hernandez}, Maria and {K. Ulland}, Tyler and Matthew Darby and Eugene Park and Farina Karim and Laura Melocchi and Rajhmun Madansein and Dullabh, {Kaylesh Jay} and Micah Dunlap and Nancy Marin-Agudelo and Takashi Ebihara and Thumbi Ndung{\textquoteright}u and Deepak Kaushal and Pym, {Alexander S.} and Kolls, {Jay K.} and Adrie Steyn and Joaqu{\'i}n Z{\'u}{\~n}iga and William Horsnell and Yokoyama, {Wayne M.} and Shalek, {Alex K.} and Kl{\o}verpris, {Henrik N.} and Marco Colonna and Alasdair Leslie and Khader, {Shabaana A.}",

year = "2019",

doi = "10.1038/s41586-019-1276-2",

language = "English",

volume = "570",

pages = "528--532",

journal = "Nature",

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T1 - Group 3 innate lymphoid cells mediate early protective immunity against tuberculosis

AU - Ardain, Amanda

AU - Domingo-Gonzalez, Racquel

AU - Das, Shibali

AU - Kazer, Samuel W.

AU - Howard, Nicole C.

AU - Singh, Alveera

AU - Ahmed, Mushtaq

AU - Nhamoyebonde, Shepherd

AU - Rangel-Moreno, Javier

AU - Ogongo, Paul

AU - Lu, Lan

AU - Ramsuran, Duran

AU - de la Luz Garcia-Hernandez, Maria

AU - K. Ulland, Tyler

AU - Darby, Matthew

AU - Park, Eugene

AU - Karim, Farina

AU - Melocchi, Laura

AU - Madansein, Rajhmun

AU - Dullabh, Kaylesh Jay

AU - Dunlap, Micah

AU - Marin-Agudelo, Nancy

AU - Ebihara, Takashi

AU - Ndung’u, Thumbi

AU - Kaushal, Deepak

AU - Pym, Alexander S.

AU - Kolls, Jay K.

AU - Steyn, Adrie

AU - Zúñiga, Joaquín

AU - Horsnell, William

AU - Yokoyama, Wayne M.

AU - Shalek, Alex K.

AU - Kløverpris, Henrik N.

AU - Colonna, Marco

AU - Leslie, Alasdair

AU - Khader, Shabaana A.

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

U2 - 10.1038/s41586-019-1276-2

DO - 10.1038/s41586-019-1276-2

M3 - Letter

C2 - 31168092

AN - SCOPUS:85066976219

SN - 0028-0836

VL - 570

SP - 528

EP - 532

JO - Nature

JF - Nature

IS - 7762

ER -

Group 3 innate lymphoid cells mediate early protective immunity against tuberculosis

Abstract

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