Natural killer cells are recruited during pulmonary tuberculosis and theirex vivoresponses to mycobacteria vary between healthy human donors in association withKIRhaplotype

Abstract

SummaryHumans vary widely in their susceptibility to tuberculosis. While only a minority will progress to disease, the majority of healthy individuals exposed to Mycobacterium tuberculosis mount an immune response that can clear or contain the infection in a quiescent form. Using immunofluorescence on human clinical samples, we identified natural killer (NK) cells infiltrating granulomatous pulmonary lesions during active disease. In order to compare the NK cell ability to react to free mycobacteria in the context of tuberculosis infection and Mycobacterium bovis BCG vaccination, NK cells were isolated from the peripheral blood of anonymous healthy human donors, and stimulated with M. tuberculosis H37Rv or M. bovis BCG. Extracellular M. tuberculosis and M. bovis BCG could equally trigger the release of IFNγ and TNFα from NK cells in the presence of IL-2. However, we found that this response varied 1000-fold between individuals (n = 52), with differences in KIR haplotype providing a significant criterion to distinguish between low and high responders. Our findings suggest that variations at the KIR locus and therefore of the NK cell repertoire may affect cytokine production in response to mycobacteria and we propose that this innate variability couldsustain different levels of susceptibility to M. tuberculosis infection.

CD4 + T-cell–independent mechanisms suppress reactivation of latent tuberculosis in a macaque model of HIV coinfection

“…These results are consistent with previous observations that macaques not only lose bacillus Calmette-Guérin vaccination-induced protective immunity upon experimental depletion of CD8 + T cells, but also reactivate Mtb infections suppressed by chemotherapy at a higher rate (13). In addition, the presence of CD3 − cells producing granzyme lends credibility to the role of NK cells in mediating control of both SIV and Mtb infection (37,38). The effector role of CD8 + T cells in the control of Mtb infection in humans has recently been described to inversely correlate with bacterial load in sputum (39), and HIV coinfection can impair Mtb-specific CD8 + T degranulation and proliferation (40).…”

Natural Killer Cells: A Coherent Model for Their Functional Role in <b><i>Mycobacterium tuberculosis</i></b> Infection

“…obs.] and others [58], and it may explain, at least in part, the discrepancies observed in different studies. The recent discovery that NK cells may express immunological memory [38,39,40] suggests the attractive hypothesis that the variability in NK cell responses could be related to differences among donors in the degree of sensitization to mycobacterial antigens, due to previous exposure to BCG vaccination or environmental mycobacteria.…”

“…Another explanation for the inter-individual variability in the NK cell responses could be related to the expression of specific human leukocyte antigen/KIR haplotypes. It has recently been proposed that KIR B haplotypes are correlated to a higher responsiveness of NK cells to extracellular mycobacteria [58]. …”

“…Moreover, it is essential to compare the number of NK cells in the peripheral blood and at sites of local infection (e.g. the pleural fluid, bronchioles and alveoli and lung tissue), as the migration of NK cells from the peripheral blood to sites of local infection, with a prevalence of CD56 bright NK cell subset in the latter, has been demonstrated [58,93]. …”

Interaction of Mycobacterium tuberculosis Cell Wall Components with the Human Natural Killer Cell Receptors NKp44 and Toll‐Like Receptor 2

“…In addition, NK cells from patients with latent TB contribute to adaptive immunity against MTB by enhancing the mycobacteria-specific CD8 + T cell effector functions [4] and by inhibiting expansion of regulatory T cells [21]. Recently, it has been reported that NK cells are recruited within mature granulomatous lesions of TB patients suggesting that they may play a role not only in the early phases of TB infection, but also at later time points [22].…”