Lung endothelial cell antigen cross-presentation to CD8+T cells drives malaria-associated lung injury

Carla Claser; Samantha Yee Teng Nguee; Akhila Balachander; Shanshan Wu Howland; Etienne Becht; Bavani Gunasegaran; Siddesh V. Hartimath; Audrey W. Q. Lee; Jacqueline Theng Theng Ho; Chee Bing Ong; Evan W. Newell; Julian Goggi; Lai Guan Ng; Laurent Renia

doi:10.1038/s41467-019-12017-8

Lung endothelial cell antigen cross-presentation to CD8+T cells drives malaria-associated lung injury

Carla Claser, Samantha Yee Teng Nguee, Akhila Balachander, Shanshan Wu Howland, Etienne Becht, Bavani Gunasegaran, Siddesh V. Hartimath, Audrey W. Q. Lee, Jacqueline Theng Theng Ho, Chee Bing Ong, Evan W. Newell, Julian Goggi, Lai Guan Ng, Laurent Renia

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Abstract

Malaria-associated acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) are life-threatening manifestations of severe malaria infections. The pathogenic mechanisms that lead to respiratory complications, such as vascular leakage, remain unclear. Here, we confirm that depleting CD8 ⁺T cells with anti-CD8β antibodies in C57BL/6 mice infected with P. berghei ANKA (PbA) prevent pulmonary vascular leakage. When we transfer activated parasite-specific CD8 ⁺T cells into PbA-infected TCRβ ^−/− mice (devoid of all T-cell populations), pulmonary vascular leakage recapitulates. Additionally, we demonstrate that PbA-infected erythrocyte accumulation leads to lung endothelial cell cross-presentation of parasite antigen to CD8 ⁺T cells in an IFNγ−dependent manner. In conclusion, pulmonary vascular damage in ALI is a consequence of IFNγ-activated lung endothelial cells capturing, processing, and cross-presenting malaria parasite antigen to specific CD8 ⁺T cells induced during infection. The mechanistic understanding of the immunopathogenesis in malaria-associated ARDS and ALI provide the basis for development of adjunct treatments.

Original language	English
Article number	4241
Pages (from-to)	1-6
Number of pages	16
Journal	Nature Communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-12017-8
Publication status	Published - 18 Sept 2019
Externally published	Yes

Bibliographical note

Copyright the Author(s) 2019. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

A correction exists for this article, and has been incorporated into the original document. The correction can be found at doi: 10.1038/s41467-019-13025-4

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Publisher version (open access)Final published version, 4.31 MBLicence: CC BY

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Claser, C., Nguee, S. Y. T., Balachander, A., Howland, S. W., Becht, E., Gunasegaran, B., Hartimath, S. V., Lee, A. W. Q., Ho, J. T. T., Ong, C. B., Newell, E. W., Goggi, J., Ng, L. G., & Renia, L. (2019). Lung endothelial cell antigen cross-presentation to CD8+T cells drives malaria-associated lung injury. Nature Communications, 10(1), 1-6. Article 4241. https://doi.org/10.1038/s41467-019-12017-8

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title = "Lung endothelial cell antigen cross-presentation to CD8+T cells drives malaria-associated lung injury",

abstract = "Malaria-associated acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) are life-threatening manifestations of severe malaria infections. The pathogenic mechanisms that lead to respiratory complications, such as vascular leakage, remain unclear. Here, we confirm that depleting CD8 +T cells with anti-CD8β antibodies in C57BL/6 mice infected with P. berghei ANKA (PbA) prevent pulmonary vascular leakage. When we transfer activated parasite-specific CD8 +T cells into PbA-infected TCRβ −/− mice (devoid of all T-cell populations), pulmonary vascular leakage recapitulates. Additionally, we demonstrate that PbA-infected erythrocyte accumulation leads to lung endothelial cell cross-presentation of parasite antigen to CD8 +T cells in an IFNγ−dependent manner. In conclusion, pulmonary vascular damage in ALI is a consequence of IFNγ-activated lung endothelial cells capturing, processing, and cross-presenting malaria parasite antigen to specific CD8 +T cells induced during infection. The mechanistic understanding of the immunopathogenesis in malaria-associated ARDS and ALI provide the basis for development of adjunct treatments. ",

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AU - Claser, Carla

AU - Nguee, Samantha Yee Teng

AU - Balachander, Akhila

AU - Howland, Shanshan Wu

AU - Becht, Etienne

AU - Gunasegaran, Bavani

AU - Hartimath, Siddesh V.

AU - Lee, Audrey W. Q.

AU - Ho, Jacqueline Theng Theng

AU - Ong, Chee Bing

AU - Newell, Evan W.

AU - Goggi, Julian

AU - Ng, Lai Guan

AU - Renia, Laurent

N1 - Copyright the Author(s) 2019. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher. A correction exists for this article, and has been incorporated into the original document. The correction can be found at doi: 10.1038/s41467-019-13025-4

PY - 2019/9/18

Y1 - 2019/9/18

N2 - Malaria-associated acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) are life-threatening manifestations of severe malaria infections. The pathogenic mechanisms that lead to respiratory complications, such as vascular leakage, remain unclear. Here, we confirm that depleting CD8 +T cells with anti-CD8β antibodies in C57BL/6 mice infected with P. berghei ANKA (PbA) prevent pulmonary vascular leakage. When we transfer activated parasite-specific CD8 +T cells into PbA-infected TCRβ −/− mice (devoid of all T-cell populations), pulmonary vascular leakage recapitulates. Additionally, we demonstrate that PbA-infected erythrocyte accumulation leads to lung endothelial cell cross-presentation of parasite antigen to CD8 +T cells in an IFNγ−dependent manner. In conclusion, pulmonary vascular damage in ALI is a consequence of IFNγ-activated lung endothelial cells capturing, processing, and cross-presenting malaria parasite antigen to specific CD8 +T cells induced during infection. The mechanistic understanding of the immunopathogenesis in malaria-associated ARDS and ALI provide the basis for development of adjunct treatments.

AB - Malaria-associated acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) are life-threatening manifestations of severe malaria infections. The pathogenic mechanisms that lead to respiratory complications, such as vascular leakage, remain unclear. Here, we confirm that depleting CD8 +T cells with anti-CD8β antibodies in C57BL/6 mice infected with P. berghei ANKA (PbA) prevent pulmonary vascular leakage. When we transfer activated parasite-specific CD8 +T cells into PbA-infected TCRβ −/− mice (devoid of all T-cell populations), pulmonary vascular leakage recapitulates. Additionally, we demonstrate that PbA-infected erythrocyte accumulation leads to lung endothelial cell cross-presentation of parasite antigen to CD8 +T cells in an IFNγ−dependent manner. In conclusion, pulmonary vascular damage in ALI is a consequence of IFNγ-activated lung endothelial cells capturing, processing, and cross-presenting malaria parasite antigen to specific CD8 +T cells induced during infection. The mechanistic understanding of the immunopathogenesis in malaria-associated ARDS and ALI provide the basis for development of adjunct treatments.

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Lung endothelial cell antigen cross-presentation to CD8+T cells drives malaria-associated lung injury

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