TIGIT is upregulated by HIV-1 infection and marks a highly functional adaptive and mature subset of natural killer cells

Vendrame, Elena; Seiler, Christof; Ranganath, Thanmayi; Zhao, Nancy Q.; Vergara, Rosemary; Alary, Michel; Labbé, Annie‐Claude; Poudrier, Johanne; Holmes, Susan; Roger, Michel; Blish, Catherine A.

doi:10.1097/qad.0000000000002488

Cited by 38 publications

(53 citation statements)

References 72 publications

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“…Among Kenyan adults, TIGIT expression was downregulated on CD56 dim cells from QFT + individuals, compared with QFT − individuals. Although no previously published studies have comprehensively evaluated TIGIT on NK cells in the setting of human Mtb infection, increased TIGIT expression on NK cells has been reported in studies of HIVinfected individuals, compared with HIV-uninfected individuals (Yin et al, 2018;Motamedi et al, 2019;Vendrame et al, 2020), indicating that TIGIT expression on NK cells may be modulated in the setting of chronic infection. Moreover, the level of expression of TIGIT on human NK cells has been associated with NK cell functional heterogeneity in healthy adults (Wang et al, 2015), and blockade of TIGIT has been reported to increase NK cell effector functions (Stanietsky et al, 2009;Wang et al, 2015;Zhang et al, 2018), thus providing rationale for exploring TIGIT as a potential immunotherapeutic target.…”

Section: Discussionmentioning

confidence: 99%

Distinct Human NK Cell Phenotypes and Functional Responses to Mycobacterium tuberculosis in Adults From TB Endemic and Non-endemic Regions

Harris

Khayumbi

Ongalo

et al. 2020

Front. Cell. Infect. Microbiol.

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Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis (TB), which leads to an estimated 1. 5 million deaths worldwide each year. Although the immune correlates of protection against Mtb infection and TB disease have not been well-defined, natural killer (NK) cells are increasingly recognized as a key component of the innate immune response to Mtb and as a link between innate and adaptive immunity. In this study, we evaluated NK cell phenotypic and functional profiles in QuantiFERON-TB (QFT) + and QFT − adults in a TB endemic setting in Kisumu, Kenya, and compared their NK cell responses to those of Mtb-naïve healthy adult controls in the U.S. We used flow cytometry to define the phenotypic profile of NK cells and identified distinct CD56 dim NK cell phenotypes that differentiated the Kenyan and U.S. groups. Additionally, among Kenyan participants, NK cells from QFT + individuals with latent Mtb infection (LTBI) were characterized by significant downregulation of the natural cytotoxicity receptor NKp46 and the inhibitory receptor TIGIT, compared with QFT − individuals. Moreover, the distinct CD56 dim phenotypic profiles in Kenyan individuals correlated with dampened NK cell responses to tumor cells and diminished activation, degranulation, and cytokine production following stimulation with Mtb antigens, compared with Mtb-naïve U.S. healthy adult controls. Taken together, these data provide evidence that the phenotypic and functional profiles of NK cells are modified in TB endemic settings and will inform future studies aimed at defining NK cell-mediated immune correlates that may be protective against acquisition of Mtb infection and progression to TB disease.

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Section: Discussionmentioning

confidence: 99%

Distinct Human NK Cell Phenotypes and Functional Responses to Mycobacterium tuberculosis in Adults From TB Endemic and Non-endemic Regions

Harris

Khayumbi

Ongalo

et al. 2020

Front. Cell. Infect. Microbiol.

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“…NK cells were purified from PBMCs by magnetic-activated isolation via negative selection (Miltenyi, Bergisch Gladbach, Germany) and stained for mass cytometry as described previously [40], using CyTOF Panel 1 (S1 Table). All antibodies were conjugated using MaxPar1 ×8 labeling kits (Fluidigm, South San Francisco, CA, USA).…”

Section: Mass Cytometry For Nk Cell Profiling Of Hesn and Healthy Benmentioning

confidence: 99%

“…Markers noted to have poor staining were excluded from subsequent analyses (FAS-L, Ki-67, KIR2DS2 and CXCR6 for Panel 1; CD11a and KIR2DS2 for Panel 2). Serial negative gating was used to identify NK cells, as described [40] (S1 Fig). Normalized signal intensities were transformed using the inverse hyperbolic sine (asinh) function with a cofactor equal to 5 to account for heteroskedasticity, prior to subsequent analyses.…”

Section: Plos Onementioning

confidence: 99%

Natural killer cell phenotype is altered in HIV-exposed seronegative women

et al. 2020

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Highly exposed seronegative (HESN) individuals present a unique setting to study mechanisms of protection against HIV acquisition. As natural killer (NK) cell activation and function have been implicated as a correlate of protection in HESN individuals, we sought to better understand the features of NK cells that may confer protection. We used mass cytometry to phenotypically profile NK cells from a cohort of Beninese sex workers and healthy controls. We found that NK cells from HESN women had increased expression of NKG2A, NKp30 and LILRB1, as well as the Fc receptor CD16, and decreased expression of DNAM-1, CD94, Siglec-7, and NKp44. Using functional assessments of NK cells from healthy donors against autologous HIV-infected CD4 + T cells, we observed that NKp30 + and Siglec-7 + cells had improved functional activity. Further, we found that NK cells from HESN women trended towards increased antibody-dependent cellular cytotoxicity (ADCC) activity; this activity correlated with increased CD16 expression. Overall, we identify features of NK cells in HESN women that may contribute to protection from HIV infection. Follow up studies with larger cohorts are warranted to confirm these findings.

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“…This is particularly relevant as our study used IL-2 activated NK cells. TIGIT + NK cells have also been previously implicated in HIV control -TIGIT expansion is markedly enhanced on NK cells in untreated HIV infection (Yin et al, 2018;Vendrame et al, 2020). We also recently demonstrated that TIGIT expression marks a population of NK cells with an adaptive phenotype with greater functional activity against HIV-infected cells as well as other stimuli (Vendrame et al, 2020).…”

Section: Discussionmentioning

confidence: 76%

“…CD56 neg NK cells are functionally impaired and thought to be exhausted, demonstrating reduced cytotoxicity and IFN-ɣ production (Hu et al, 1995;Mavilio et al, 2005;Milush et al, 2013). In addition, the expression of the inhibitory receptor Siglec-7 (Brunetta et al, 2009), as well as the expression of the activating receptors NKp30, NKp44 and NKp46 (Mavilio et al, 2003), are decreased in chronic, viraemic HIV infection, whereas the expression of the inhibitory receptor TIGIT is increased (Yin et al, 2018;Vendrame et al, 2020). After treatment with antiretroviral therapy (ART), the patterns of CD56 + and CD56 neg NK cell subsets are restored to levels similar to seronegative, healthy individuals (Mavilio et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Treated HIV Infection Alters Phenotype But Not HIV-specific Function of Peripheral Blood Natural Killer Cells

Zhao

Ferreira

Grant

et al. 2020

Preprint

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ABSTRACTNatural killer (NK) cells are the predominant antiviral cells of the innate immune system, and may play an important role in acquisition and disease progression of HIV. While untreated HIV infection is associated with distinct alterations in the peripheral blood NK cell repertoire, less is known about how NK phenotype is altered in the setting of long-term viral suppression with antiretroviral therapy (ART), as well as how NK memory can impact functional responses. As such, we sought to identify changes in NK cell phenotype and function using high-dimensional mass cytometry to simultaneously analyze both surface and functional marker expression of peripheral blood NK cells in a cohort of ART-suppressed, HIV+ patients and HIV-healthy controls. We found that the NK cell repertoire following IL-2 treatment was altered in individuals with treated HIV infection compared to healthy controls, with increased expression of markers including NKG2C and CD2, and decreased expression of CD244 and NKp30. Using co-culture assays with autologous, in vitro HIV-infected CD4 T cells, we identified a subset of NK cells with enhanced responsiveness to HIV-1-infected cells, but no differences in the magnitude of anti-HIV NK cell responses between the HIV+ and HIV-groups. In addition, by profiling of NK cell receptors on responding cells, we found similar phenotypes of HIV-responsive NK cell subsets in both groups. Lastly, we identified clusters of NK cells that are altered in individuals with treated HIV infection compared to healthy controls, but found that these clusters are distinct from those that respond to HIV in vitro. As such, we conclude that while chronic, treated HIV infection induces a reshaping of the IL-2-stimulated peripheral blood NK cell repertoire, it does so in a way that does not make the repertoire more HIV-specific.

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TIGIT is upregulated by HIV-1 infection and marks a highly functional adaptive and mature subset of natural killer cells

Cited by 38 publications

References 72 publications

Distinct Human NK Cell Phenotypes and Functional Responses to Mycobacterium tuberculosis in Adults From TB Endemic and Non-endemic Regions

Distinct Human NK Cell Phenotypes and Functional Responses to Mycobacterium tuberculosis in Adults From TB Endemic and Non-endemic Regions

Natural killer cell phenotype is altered in HIV-exposed seronegative women

Treated HIV Infection Alters Phenotype But Not HIV-specific Function of Peripheral Blood Natural Killer Cells

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