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Quantitative and qualitative iNKT repertoire associations with disease susceptibility and outcome in macaque tuberculosis infection

Quantitative and qualitative iNKT repertoire associations with disease susceptibility and outcome in macaque tuberculosis infection
Quantitative and qualitative iNKT repertoire associations with disease susceptibility and outcome in macaque tuberculosis infection
Correlates of immune protection that reliably predict vaccine efficacy against Mycobacterium tuberculosis (Mtb) infection are urgently needed. Invariant NKT cells (iNKTs) are CD1d-dependent innate T cells that augment host antimicrobial immunity through production of cytokines, including interferon (IFN)-γ and tumour necrosis factor (TNF)-α. We determined peripheral blood iNKT numbers, their proliferative responses and iNKT subset proportions after in vitro antigen expansion by α-galactosylceramide (αGC) in a large cohort of mycobacteria-naïve non-human primates, and macaques from Bacillus Calmette-Guerin (BCG) vaccine and Mtb challenge studies. Animals studied included four genetically distinct groups of macaques within cynomolgus and rhesus species that differ in their susceptibility to Mtb infection. We demonstrate significant differences in ex vivo iNKT frequency between groups, which trends towards an association with susceptibility to Mtb, but no significant difference in overall iNKT proliferative responses. Susceptible animals exhibited a skewed CD4+/CD8+ iNKT subset ratio in comparison to more Mtb-resistant groups. Correlation of iNKT subsets post BCG vaccination with clinical disease manifestations following Mtb challenge in the Chinese cynomolgus cynomolgus and Indian rhesus macaques identified a consistent trend linking increased CD8+ iNKTs with favourable disease outcome. Finally, a similar iNKT profile was conferred by BCG vaccination in rhesus macaques. Our study provides the first detailed characterisation of iNKT cells in macaque tuberculosis infection, suggesting that iNKT repertoire differences may impact on disease outcome, which warrants further investigation.
1472-9792
86-95
Chancellor, Andrew
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White, Andrew
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Tocheva, Anna S.
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Fenn, Joe R.
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Dennis, Mike
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Tezera, Liku
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Singhania, Akul
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Elliott, Timothy
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Tebruegge, Marc
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Elkington, Paul
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Gadola, Stephan D.
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Sharpe, Sally
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Mansour, Salah
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Chancellor, Andrew
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White, Andrew
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Tocheva, Anna S.
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Fenn, Joe R.
c083b739-aa79-4341-8d30-d59023e7b71b
Dennis, Mike
d1e82429-ee65-448a-8ed0-01c7d9b8e35d
Tezera, Liku
c5598dbf-23a8-4934-96a4-7c783bf9e776
Singhania, Akul
322f628d-5374-49ec-b7d7-13bb3885d636
Elliott, Timothy
16670fa8-c2f9-477a-91df-7c9e5b453e0e
Tebruegge, Marc
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Elkington, Paul
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Gadola, Stephan D.
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Sharpe, Sally
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Mansour, Salah
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Chancellor, Andrew, White, Andrew, Tocheva, Anna S., Fenn, Joe R., Dennis, Mike, Tezera, Liku, Singhania, Akul, Elliott, Timothy, Tebruegge, Marc, Elkington, Paul, Gadola, Stephan D., Sharpe, Sally and Mansour, Salah (2017) Quantitative and qualitative iNKT repertoire associations with disease susceptibility and outcome in macaque tuberculosis infection. Tuberculosis, 105, 86-95. (doi:10.1016/j.tube.2017.04.011).

Record type: Article

Abstract

Correlates of immune protection that reliably predict vaccine efficacy against Mycobacterium tuberculosis (Mtb) infection are urgently needed. Invariant NKT cells (iNKTs) are CD1d-dependent innate T cells that augment host antimicrobial immunity through production of cytokines, including interferon (IFN)-γ and tumour necrosis factor (TNF)-α. We determined peripheral blood iNKT numbers, their proliferative responses and iNKT subset proportions after in vitro antigen expansion by α-galactosylceramide (αGC) in a large cohort of mycobacteria-naïve non-human primates, and macaques from Bacillus Calmette-Guerin (BCG) vaccine and Mtb challenge studies. Animals studied included four genetically distinct groups of macaques within cynomolgus and rhesus species that differ in their susceptibility to Mtb infection. We demonstrate significant differences in ex vivo iNKT frequency between groups, which trends towards an association with susceptibility to Mtb, but no significant difference in overall iNKT proliferative responses. Susceptible animals exhibited a skewed CD4+/CD8+ iNKT subset ratio in comparison to more Mtb-resistant groups. Correlation of iNKT subsets post BCG vaccination with clinical disease manifestations following Mtb challenge in the Chinese cynomolgus cynomolgus and Indian rhesus macaques identified a consistent trend linking increased CD8+ iNKTs with favourable disease outcome. Finally, a similar iNKT profile was conferred by BCG vaccination in rhesus macaques. Our study provides the first detailed characterisation of iNKT cells in macaque tuberculosis infection, suggesting that iNKT repertoire differences may impact on disease outcome, which warrants further investigation.

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Chancellor et al, manuscript - Accepted Manuscript
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More information

Accepted/In Press date: 19 April 2017
e-pub ahead of print date: 28 April 2017
Published date: July 2017
Organisations: Cancer Sciences, Allergy & Inflammation Research, Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 408249
URI: https://eprints.soton.ac.uk/id/eprint/408249
ISSN: 1472-9792
PURE UUID: af6a54e1-0134-43f5-a938-a6f807b08f67
ORCID for Liku Tezera: ORCID iD orcid.org/0000-0002-7898-6709
ORCID for Timothy Elliott: ORCID iD orcid.org/0000-0003-1097-0222
ORCID for Paul Elkington: ORCID iD orcid.org/0000-0003-0390-0613
ORCID for Salah Mansour: ORCID iD orcid.org/0000-0002-5982-734X

Catalogue record

Date deposited: 18 May 2017 04:02
Last modified: 19 Nov 2019 06:11

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