Abstract
PurposeTuberculosis (TB) is the leading cause of infectious disease related mortality, and only 10% of the infected individuals develop active disease. The likelihood of progression of latent tuberculosis infection (LTBI) to active TB disease is high in HIV infected individuals. Identification of HIV+ individuals at risk would allow treating targeted population, facilitating completion of therapy for LTBI and prevention of TB development. NK cells have an important role in T cell independent immunity against TB, but the exact role of NK cell subsets in LTBI and HIV is not well characterized.MethodsIn this study, we compared the expansion and function of memory like NK cells from HIV-LTBI+ individuals and treatment naïve HIV+LTBI+ patients in response to Mtb antigens ESAT-6 and CFP-10.ResultsIn freshly isolated PBMCs, percentages of CD3-CD56+ NK cells were similar in HIV+LTBI+ patients and healthy HIV-LTBI+ individuals. However, percentages of CD3-CD56+CD16+ NK cells were higher in healthy HIV-LTBI+ individuals compared to HIV+LTBI+ patients. HIV infection also inhibited the expansion of memory like NK cells, production of IL-32α, IL-15 and IFN-γ in response to Mtb antigens in LTBI+ individuals.ConclusionWe studied phenotypic, functional subsets and activation of memory like-NK cells during HIV infection and LTBI. We observed that HIV+LTBI+ patients demonstrated suboptimal NK cell and monocyte interactions in response to Mtb, leading to reduced IL-15, IFN-γ and granzyme B and increased CCL5 production. Our study highlights the effect of HIV and LTBI on modulation of NK cell activity to understand their role in development of interventions to prevent progression to TB in high risk individuals.
Highlights
Mycobacterium tuberculosis (Mtb) kills about 1.5 million individuals each year globally [1]. 10% of individuals with latent tuberculosis infection (LTBI), are at risk of developing active TB
Functional subsets and activation of memory like-Natural Killer (NK) cells during Human Immunodeficiency Virus (HIV) infection and LTBI
Percentages of CD3-CD56+CD16+ cells were higher in HIV-LTBI+ than HIV-LTBI- individuals (Fig 1B, p = 0.002) and HIV+LTBI+ patients (Fig 1B, p = 0.0005); in HIV-LTBI- individuals compared to HIV+LTBI- patients (Fig 1B, p
Summary
Mycobacterium tuberculosis (Mtb) kills about 1.5 million individuals each year globally [1]. 10% of individuals with latent tuberculosis infection (LTBI), are at risk of developing active TB. 10% of individuals with latent tuberculosis infection (LTBI), are at risk of developing active TB. Identification of HIV+ individuals with LTBI who are at increased risk would allow targeted treatment to prevent development of active TB. To identify these individuals, it is important to pinpoint the nature of defects in immune responses that lead to development of active TB in HIV+LTBI+ patients. Natural Killer (NK) cells are multifunctional CD3-CD56+ lymphocytes and important mediators of innate immune responses playing a key role in clearance of viruses and other intracellular pathogens [4, 5]. We demonstrated that IL-21 dependent expansion of memory-like NK cells is crucial for inducing protective immunity against Mtb post BCG vaccination in humans, as well as mice [10]
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