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

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 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.

Multimodal profiling of lung granulomas reveals cellular correlates of tuberculosis control

“…Data from human and animal models (including NHPs) suggest an important role for diverse lymphocyte populations in controlling Mtb infection. In addition to compelling evidence for the importance of conventional CD4+ and CD8+ T cells (Chen et al, 2009;Foreman et al, 2016;Lin and Flynn, 2015;Lin et al, 2012;Mogues et al, 2001), other lymphocyte populations have been implicated in control including gamma delta (γδ) T cells (Ogongo et al, 2020;Shen et al, 2019), iNKT cells (Arora et al, 2013;Chackerian et al, 2002;Chancellor et al, 2017), donor-unrestricted T cells such as MAITs (Joosten et al, 2019), innate lymphoid cells (ILC) (Ardain et al, 2019) and cytotoxic lymphocytes including NK cells (Lin and Flynn, 2015;Portevin et al, 2012;Roy Chowdhury et al, 2018).…”

Mucosal-associated invariant and γδ T cell subsets respond to initial Mycobacterium tuberculosis infection

“…iNKT cells have been shown to inhibit intracellular growth of Mtb through granulocyte-macrophage-CSF (GM-CSF) production (16). In a macaque model, CD8 + iNKT cell abundance directly correlated with a resistance phenotype to Mtb challenge (17). Whereas iNKT cells have been shown to be depleted from the blood in active pulmonary TB (18)(19)(20), their role during early responses to initial human Mtb infection is not well understood.…”

Latent Mycobacterium tuberculosis Infection Is Associated With a Higher Frequency of Mucosal-Associated Invariant T and Invariant Natural Killer T Cells

“…Results from non-human primate (NHP) animal models of Mtb infection suggest that CD8+ iNKT cells can play a protective role in preventing Mtb pathology ( 31 ), and MAIT cells were activated following BCG vaccination and Mtb infection ( 32 ). In mouse models, both iNKT and MAIT cells reduced bacterial burden following Mtb infection ( 13 , 33 ).…”