Natural killer cell activation enhances immune pathology and promotes chronic infection by limiting CD8 + T-cell immunity

Philipp A. Lang; Karl S. Lang; Haifeng C. Xu; Melanie Grusdat; Ian A. Parish; Mike Recher; Alisha R. Elford; Salim Dhanji; Namir Shaabani; Charles W. Tran; Dilan Dissanayake; Ramtin Rahbar; Magar Ghazarian; Anne Brüstle; Jason Fine; Peter Chen; Casey T. Weaver; Christoph Klose; Andreas Diefenbach; Dieter Häussinger; James R. Carlyle; Susan M. Kaech; Tak W. Mak; Pamela S. Ohashi

doi:10.1073/pnas.1118834109

Natural killer cell activation enhances immune pathology and promotes chronic infection by limiting CD8 ⁺ T-cell immunity

Philipp A. Lang, Karl S. Lang, Haifeng C. Xu, Melanie Grusdat, Ian A. Parish, Mike Recher, Alisha R. Elford, Salim Dhanji, Namir Shaabani, Charles W. Tran, Dilan Dissanayake, Ramtin Rahbar, Magar Ghazarian, Anne Brüstle, Jason Fine, Peter Chen, Casey T. Weaver, Christoph Klose, Andreas Diefenbach, Dieter HäussingerJames R. Carlyle, Susan M. Kaech, Tak W. Mak, Pamela S. Ohashi^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Research › peer-review

273 Citations (Scopus)

Abstract

Infections with HIV, hepatitis B virus, and hepatitis C virus can turn into chronic infections, which currently affect more than 500 million patients worldwide. It is generally thought that virus-mediated T-cell exhaustion limits T-cell function, thus promoting chronic disease.Here we demonstrate that natural killer (NK) cells have a negative impact on the development of T-cell immunity by using the murine lymphocytic choriomeningitis virus.NK cell-deficient (Nfil3 ^-/-, E4BP4 ^-/-)mice exhibited a higher virus-specific T-cell response. In addition, NK cell depletion caused enhanced T-cell immunity in WT mice, which led to rapid virus control and prevented chronic infection in lymphocytic choriomeningitis virus clone 13- and reduced viral load in DOCILEinfected animals. Further experiments showed that NKG2D triggered regulatory NK cell functions, which were mediated by perforin, and limited T-cell responses. Therefore,we identified an important role of regulatory NK cells in limiting T-cell immunity during virus infection.

Original language	English
Pages (from-to)	1210-1215
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	109
Issue number	4
DOIs	https://doi.org/10.1073/pnas.1118834109
Publication status	Published - 24 Jan 2012
Externally published	Yes

Keywords

Effector T cells
NK cell activation
Regulatory innate immunity
Virus elimination
Virus persistence

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10.1073/pnas.1118834109

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Lang, P. A., Lang, K. S., Xu, H. C., Grusdat, M., Parish, I. A., Recher, M., Elford, A. R., Dhanji, S., Shaabani, N., Tran, C. W., Dissanayake, D., Rahbar, R., Ghazarian, M., Brüstle, A., Fine, J., Chen, P., Weaver, C. T., Klose, C., Diefenbach, A., ... Ohashi, P. S. (2012). Natural killer cell activation enhances immune pathology and promotes chronic infection by limiting CD8 ⁺ T-cell immunity. Proceedings of the National Academy of Sciences of the United States of America, 109(4), 1210-1215. https://doi.org/10.1073/pnas.1118834109

@article{2aed6dcb5ea24b8c92af7490cba9d845,

title = "Natural killer cell activation enhances immune pathology and promotes chronic infection by limiting CD8 + T-cell immunity",

abstract = "Infections with HIV, hepatitis B virus, and hepatitis C virus can turn into chronic infections, which currently affect more than 500 million patients worldwide. It is generally thought that virus-mediated T-cell exhaustion limits T-cell function, thus promoting chronic disease.Here we demonstrate that natural killer (NK) cells have a negative impact on the development of T-cell immunity by using the murine lymphocytic choriomeningitis virus.NK cell-deficient (Nfil3 -/-, E4BP4 -/-)mice exhibited a higher virus-specific T-cell response. In addition, NK cell depletion caused enhanced T-cell immunity in WT mice, which led to rapid virus control and prevented chronic infection in lymphocytic choriomeningitis virus clone 13- and reduced viral load in DOCILEinfected animals. Further experiments showed that NKG2D triggered regulatory NK cell functions, which were mediated by perforin, and limited T-cell responses. Therefore,we identified an important role of regulatory NK cells in limiting T-cell immunity during virus infection.",

keywords = "Effector T cells, NK cell activation, Regulatory innate immunity, Virus elimination, Virus persistence",

author = "Lang, {Philipp A.} and Lang, {Karl S.} and Xu, {Haifeng C.} and Melanie Grusdat and Parish, {Ian A.} and Mike Recher and Elford, {Alisha R.} and Salim Dhanji and Namir Shaabani and Tran, {Charles W.} and Dilan Dissanayake and Ramtin Rahbar and Magar Ghazarian and Anne Br{\"u}stle and Jason Fine and Peter Chen and Weaver, {Casey T.} and Christoph Klose and Andreas Diefenbach and Dieter H{\"a}ussinger and Carlyle, {James R.} and Kaech, {Susan M.} and Mak, {Tak W.} and Ohashi, {Pamela S.}",

year = "2012",

month = jan,

day = "24",

doi = "10.1073/pnas.1118834109",

language = "English",

volume = "109",

pages = "1210--1215",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

issn = "0027-8424",

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Lang, PA, Lang, KS, Xu, HC, Grusdat, M, Parish, IA, Recher, M, Elford, AR, Dhanji, S, Shaabani, N, Tran, CW, Dissanayake, D, Rahbar, R, Ghazarian, M, Brüstle, A, Fine, J, Chen, P, Weaver, CT, Klose, C, Diefenbach, A, Häussinger, D, Carlyle, JR, Kaech, SM, Mak, TW & Ohashi, PS 2012, 'Natural killer cell activation enhances immune pathology and promotes chronic infection by limiting CD8 ⁺ T-cell immunity', Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 4, pp. 1210-1215. https://doi.org/10.1073/pnas.1118834109

Natural killer cell activation enhances immune pathology and promotes chronic infection by limiting CD8 ⁺ T-cell immunity. / Lang, Philipp A.; Lang, Karl S.; Xu, Haifeng C. et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 4, 24.01.2012, p. 1210-1215.

Research output: Contribution to journal › Article › Research › peer-review

TY - JOUR

T1 - Natural killer cell activation enhances immune pathology and promotes chronic infection by limiting CD8 + T-cell immunity

AU - Lang, Philipp A.

AU - Lang, Karl S.

AU - Xu, Haifeng C.

AU - Grusdat, Melanie

AU - Parish, Ian A.

AU - Recher, Mike

AU - Elford, Alisha R.

AU - Dhanji, Salim

AU - Shaabani, Namir

AU - Tran, Charles W.

AU - Dissanayake, Dilan

AU - Rahbar, Ramtin

AU - Ghazarian, Magar

AU - Brüstle, Anne

AU - Fine, Jason

AU - Chen, Peter

AU - Weaver, Casey T.

AU - Klose, Christoph

AU - Diefenbach, Andreas

AU - Häussinger, Dieter

AU - Carlyle, James R.

AU - Kaech, Susan M.

AU - Mak, Tak W.

AU - Ohashi, Pamela S.

PY - 2012/1/24

Y1 - 2012/1/24

N2 - Infections with HIV, hepatitis B virus, and hepatitis C virus can turn into chronic infections, which currently affect more than 500 million patients worldwide. It is generally thought that virus-mediated T-cell exhaustion limits T-cell function, thus promoting chronic disease.Here we demonstrate that natural killer (NK) cells have a negative impact on the development of T-cell immunity by using the murine lymphocytic choriomeningitis virus.NK cell-deficient (Nfil3 -/-, E4BP4 -/-)mice exhibited a higher virus-specific T-cell response. In addition, NK cell depletion caused enhanced T-cell immunity in WT mice, which led to rapid virus control and prevented chronic infection in lymphocytic choriomeningitis virus clone 13- and reduced viral load in DOCILEinfected animals. Further experiments showed that NKG2D triggered regulatory NK cell functions, which were mediated by perforin, and limited T-cell responses. Therefore,we identified an important role of regulatory NK cells in limiting T-cell immunity during virus infection.

AB - Infections with HIV, hepatitis B virus, and hepatitis C virus can turn into chronic infections, which currently affect more than 500 million patients worldwide. It is generally thought that virus-mediated T-cell exhaustion limits T-cell function, thus promoting chronic disease.Here we demonstrate that natural killer (NK) cells have a negative impact on the development of T-cell immunity by using the murine lymphocytic choriomeningitis virus.NK cell-deficient (Nfil3 -/-, E4BP4 -/-)mice exhibited a higher virus-specific T-cell response. In addition, NK cell depletion caused enhanced T-cell immunity in WT mice, which led to rapid virus control and prevented chronic infection in lymphocytic choriomeningitis virus clone 13- and reduced viral load in DOCILEinfected animals. Further experiments showed that NKG2D triggered regulatory NK cell functions, which were mediated by perforin, and limited T-cell responses. Therefore,we identified an important role of regulatory NK cells in limiting T-cell immunity during virus infection.

KW - Effector T cells

KW - NK cell activation

KW - Regulatory innate immunity

KW - Virus elimination

KW - Virus persistence

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U2 - 10.1073/pnas.1118834109

DO - 10.1073/pnas.1118834109

M3 - Article

C2 - 22167808

AN - SCOPUS:84863011076

SN - 0027-8424

VL - 109

SP - 1210

EP - 1215

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 4

ER -

Natural killer cell activation enhances immune pathology and promotes chronic infection by limiting CD8 ⁺ T-cell immunity

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