BCG-induced trained immunity in NK cells: Role for non-specific protection to infection
Introduction
The traditional paradigm in immunology is that innate immunity – as opposed to adaptive immunity – is static, and does not adapt after encountering an external stimulus to an enhanced functional state. However, we have recently shown that Bacillus Calmette–Guerin (BCG) [1] and Candida albicans [2] can induce enhanced non-specific protection to infections though epigenetic programming of monocytes, and we proposed the term ‘trained immunity’ for this effect [3].
Natural killer (NK) cells are an important cellular component of innate immune system. Interestingly, recent studies have shown that mouse and human NK cells exhibit adaptive memory-like properties, as they can be primed for enhanced IFNγ production upon restimulation [4], [5], [6], [7]. O'Leary et al. were the first to report that mouse NK cells may have recall responses to haptens during a delayed hypersensitivity response, a phenomenon previously attributed to T cells [4]. Later it was shown that initial stimulation of murine and human NK cells with interleukin 12 and 18 (IL12 and IL18) leads to increased IFNγ production after restimulation with cytokines or activating receptor ligation up to three weeks afterwards [5], [6]. In addition, Sun et al. described murine ‘memory’ NK cells with enhanced reaction upon restimulation, which are present after an initial infection with murine Cytomegalovirus (MCMV) [7].
These studies have shown adaptive characteristics of NK cells, with increased IFNɣ production upon re-exposure to cells with the same stimulus. In trained immunity, however, we observe that re-exposure to both the same or unrelated stimuli induce an enhanced secondary response, due to the non-specific nature of epigenetic priming of the cells [1], [2]. Moreover, we have recently shown that trained immunity of monocytes induced by BCG vaccination lasts up to one year after the vaccination [8], and it is tempting to regard this effect as a mechanism for the non-specific (heterologous) protective effects of BCG vaccination [9]. Considering the memory-like characteristics described for NK cells, in the present study we tested the hypothesis that NK cells also contribute to trained immunity after BCG vaccination in both human volunteers and in experimental murine disseminated candidiasis.
Section snippets
Subjects
Twenty-nine individuals (age range 20–36 years) scheduled to receive a BCG vaccination at the public health service because of travel or work in TB-endemic countries (starting after the study was finished) were included in the study. Blood was drawn before BCG vaccination, as well as two weeks and three months afterwards. In the first twenty volunteers the cytokine measurements were done on total PBMCs, therefore an extra nine volunteers were recruited to determine the role of NK cells. There
BCG does not change the proportion of NK cell subsets
In a first set of experiments, we examined possible changes in NK cell subsets following BCG vaccination. So far, no specific phenotypic marker has been described for memory or memory-like NK cells. For increased IFNγ production there are some candidate markers that have an established correlation with human NK cell IFNγ production, such as CD94, CD69, CD159a and CD159c [6]. We decided to include some of these markers and in addition some novel activity and inhibitory markers of NK cells. NK
Discussion
In the present study we show that BCG vaccination in healthy volunteers leads to an increased proinflammatory cytokine production by NK cells in response to mycobacteria, as well as to unrelated bacterial and fungal pathogens. This effect, most profoundly seen with IL1β, lasts for at least three months, in contrast to classical non-specific activation of innate immunity, but is not accompanied by changes in NK cell subset distribution or expression of cell surface markers. These effects of BCG
Funding
This work was supported by a Vici Grant of the Netherlands Organization for Scientific Research [to M.G.N.], a Vidi Grant of the Netherlands Organization for Scientific Research [to R.v.C] and by grants from the US National Institutes of Health; and the Helmsley Trust [AI 062773, DK 043351 and DK 83756 to R.J.X.].
The following are the supplementary data related to this article.
Conflict of interest statement
The authors declare that there are no conflicts of interest.
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