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Heterogeneous yet stable V?2(+) T-cell profiles define distinct cytotoxic effector potentials in healthy human individuals.

ABSTRACT: Human ?? T cells display potent responses to pathogens and malignancies. Of particular interest are those expressing a ?? T-cell receptor (TCR) incorporating TCR?-chain variable-region-2 [V?2(+)], which are activated by pathogen-derived phosphoantigens (pAgs), or host-derived pAgs that accumulate in transformed cells or in cells exposed to aminobisphosphonates. Once activated, V?2(+) T cells exhibit multiple effector functions that have made them attractive candidates for immunotherapy. Despite this, clinical trials have reported mixed patient responses, highlighting a need for better understanding of V?2(+) T-cell biology. Here, we reveal previously unappreciated functional heterogeneity between the V?2(+) T-cell compartments of 63 healthy individuals. In this cohort, we identify distinct "V?2 profiles" that are stable over time; that do not correlate with age, gender, or history of phosphoantigen activation; and that develop after leaving the thymus. Multiple analyses suggest these V?2 profiles consist of variable proportions of two dominant but contrasting V?2(+) T-cell subsets that have divergent transcriptional programs and that display mechanistically distinct cytotoxic potentials. Importantly, an individual's V?2 profile predicts defined effector capacities, demonstrated by contrasting mechanisms and efficiencies of killing of a range of tumor cell lines. In short, these data support patient stratification to identify individuals with V?2 profiles that have effector mechanisms compatible with tumor killing and suggest that tailored V?2-profile-specific activation protocols may maximize the chances of future treatment success.

SUBMITTER: Ryan PL

PROVIDER: S-EPMC5167212 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Heterogeneous yet stable Vδ2(+) T-cell profiles define distinct cytotoxic effector potentials in healthy human individuals.

Ryan Paul L PL Sumaria Nital N Holland Christopher J CJ Bradford Claire M CM Izotova Natalia N Grandjean Capucine L CL Jawad Ali S AS Bergmeier Lesley A LA Pennington Daniel J DJ

Proceedings of the National Academy of Sciences of the United States of America 20161128 50

Human γδ T cells display potent responses to pathogens and malignancies. Of particular interest are those expressing a γδ T-cell receptor (TCR) incorporating TCRδ-chain variable-region-2 [Vδ2<sup>(+)</sup>], which are activated by pathogen-derived phosphoantigens (pAgs), or host-derived pAgs that accumulate in transformed cells or in cells exposed to aminobisphosphonates. Once activated, Vδ2<sup>(+)</sup> T cells exhibit multiple effector functions that have made them attractive candidates for i ...[more]

PMID: 27911793

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Project description:ImportanceAnemia, defined as low hemoglobin (Hb) concentration insufficient to meet an individual's physiological needs, is the most common blood condition worldwide.ObjectiveTo evaluate the current World Health Organization (WHO) Hb cutoffs for defining anemia among persons who are apparently healthy and to assess threshold validity with a biomarker of tissue iron deficiency and physiological indicator of erythropoiesis (soluble transferrin receptor [sTfR]) using multinational data.Design, setting, and participantsIn this cross-sectional study, data were collected and evaluated from 30 household, population-based nutrition surveys of preschool children aged 6 to 59 months and nonpregnant women aged 15 to 49 years during 2005 to 2016 across 25 countries. Data analysis was performed from March 2020 to April 2021.ExposureAnemia defined according to WHO Hb cutoffs.Main outcomes and measuresTo define the healthy population, persons with iron deficiency (ferritin <12 ng/mL for children or <15 ng/mL for women), vitamin A deficiency (retinol-binding protein or retinol <20.1 μg/dL), inflammation (C-reactive protein >0.5 mg/dL or α-1-acid glycoprotein >1 g/L), or known malaria were excluded. Survey-specific, pooled Hb fifth percentile cutoffs were estimated. Among individuals with Hb and sTfR data, Hb-for-sTfR curve analysis was conducted to identify Hb inflection points that reflect tissue iron deficiency and increased erythropoiesis induced by anemia.ResultsA total of 79 950 individuals were included in the original surveys. The final healthy sample was 13 445 children (39.9% of the original sample of 33 699 children; 6750 boys [50.2%]; mean [SD] age 32.9 [16.0] months) and 25 880 women (56.0% of the original sample of 46 251 women; mean [SD] age, 31.0 [9.5] years). Survey-specific Hb fifth percentile among children ranged from 7.90 g/dL (95% CI, 7.54-8.26 g/dL in Pakistan) to 11.23 g/dL (95% CI, 11.14-11.33 g/dL in the US), and among women from 8.83 g/dL (95% CI, 7.77-9.88 g/dL in Gujarat, India) to 12.09 g/dL (95% CI, 12.00-12.17 g/dL in the US). Intersurvey variance around the Hb fifth percentile was low (3.5% for women and 3.6% for children). Pooled fifth percentile estimates were 9.65 g/dL (95% CI, 9.26-10.04 g/dL) for children and 10.81 g/dL (95% CI, 10.35-11.27 g/dL) for women. The Hb-for-sTfR curve demonstrated curvilinear associations with sTfR inflection points occurring at Hb of 9.61 g/dL (95% CI, 9.55-9.67 g/dL) among children and 11.01 g/dL (95% CI, 10.95-11.09 g/dL) among women.Conclusions and relevanceCurrent WHO cutoffs to define anemia are higher than the pooled fifth percentile of Hb among persons who are outwardly healthy and from nearly all survey-specific estimates. The lower proposed Hb cutoffs are statistically significant but also reflect compensatory increased erythropoiesis. More studies based on clinical outcomes could further confirm the validity of these Hb cutoffs for anemia.

Project description:Background: Sarcoidosis and tuberculosis share similarities in clinical manifestations and histopathological features. We aimed to identify the microRNA (miRNA) profiles of the lymph nodes of individuals with sarcoidosis and of those with tuberculous lymphadenitis to investigate the value of miRNAs in the differential diagnosis of sarcoidosis and tuberculous lymphadenitis. Methods: The miRNA profiles of the lymph nodes of individuals with sarcoidosis, those with tuberculous lymphadenitis (TBLN) and controls were detected by miRNA microarray analysis in the age- and sex-matched development group of the controls (n = 3), patients with TBLN (n = 3) and patients with sarcoidosis (n = 3), and the results were validated by quantitative real-time polymerase chain reaction in the validation group of the controls (n = 30), TBLN (n = 30) and patients with sarcoidosis (n = 31). The relationship between miRNA expression and the clinical parameters of sarcoidosis was analyzed. Results: miR-145, miR-185-5p, miR-301, miR-425-5P, miR-449b and miR-885-5P were differentially expressed between individuals with sarcoidosis and controls (P < 0.0001, P < 0.0001, P = 0.0008, P = 0.0002, P = 0.0018, and P < 0.0001, respectively), and the same six miRNAs were differentially expressed between individuals with tuberculous lymphadenitis and controls (P = 0.0002, P = 0.0004, P = 0.0238, P = 0.0006, P = 0.0149, and P = 0.0045, respectively). miR-185-5p was differentially expressed between individuals with tuberculous lymphadenitis and those with sarcoidosis (P = 0.0101). The area under the receiver operating characteristic curve calculated for miR-185-5p was 0.6860, and the sensitivity and specificity of miR-185-5p for the differential diagnosis of sarcoidosis from TBLN were 61 and 80%, respectively. The levels of miR-145, miR-301, miR-425-5P, and miR-885-5P were positively correlated with CD4+/CD8+ T lymphocytes in bronchoalveolar lavage fluid. Conclusions: miRNAs in lymph nodes show similar expression patterns between individuals with sarcoidosis and those with tuberculous lymphadenitis, which were experimentally selected. miR-185-5p in the lymph nodes can be used as an auxiliary marker for the differential diagnosis of sarcoidosis and tuberculous lymphadenitis.

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Heterogeneous yet stable V?2(+) T-cell profiles define distinct cytotoxic effector potentials in healthy human individuals.

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Heterogeneous yet stable Vδ2(+) T-cell profiles define distinct cytotoxic effector potentials in healthy human individuals.

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