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Tissue-Specific Distribution of iNKT Cells Impacts Their Cytokine Response.

ABSTRACT: Three subsets of invariant natural killer T (iNKT) cells have been identified, NKT1, NKT2, and NKT17, which produce distinct cytokines when stimulated, but little is known about their localization. Here, we have defined the anatomic localization and systemic distribution of these subsets and measured their cytokine production. Thymic NKT2 cells that produced interleukin-4 (IL-4) at steady state were located in the medulla and conditioned medullary thymocytes. NKT2 cells were abundant in the mesenteric lymph node (LN) of BALB/c mice and produced IL-4 in the T cell zone that conditioned other lymphocytes. Intravenous injection of ?-galactosylceramide activated NKT1 cells with vascular access, but not LN or thymic NKT cells, resulting in systemic interferon-? and IL-4 production, while oral ?-galactosylceramide activated NKT2 cells in the mesenteric LN, resulting in local IL-4 release. These findings indicate that the localization of iNKT cells governs their cytokine response both at steady state and upon activation.

SUBMITTER: Lee YJ

PROVIDER: S-EPMC4575275 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Tissue-Specific Distribution of iNKT Cells Impacts Their Cytokine Response.

Lee You Jeong YJ Wang Haiguang H Starrett Gabriel J GJ Phuong Vanessa V Jameson Stephen C SC Hogquist Kristin A KA

Immunity 20150908 3

Three subsets of invariant natural killer T (iNKT) cells have been identified, NKT1, NKT2, and NKT17, which produce distinct cytokines when stimulated, but little is known about their localization. Here, we have defined the anatomic localization and systemic distribution of these subsets and measured their cytokine production. Thymic NKT2 cells that produced interleukin-4 (IL-4) at steady state were located in the medulla and conditioned medullary thymocytes. NKT2 cells were abundant in the mese ...[more]

PMID: 26362265

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Project description:Glioblastomas are aggressive primary brain tumors known for their inter- and intratumor heterogeneity. This disease is uniformly fatal, with intratumor heterogeneity the major reason for treatment failure and recurrence. Just like the nature vs nurture debate, heterogeneity can arise from intrinsic or environmental influences. Whilst it is impossible to clinically separate observed behavior of cells from their environmental context, using a mathematical framework combined with multiscale data gives us insight into the relative roles of variation from different sources. To better understand the implications of intratumor heterogeneity on therapeutic outcomes, we created a hybrid agent-based mathematical model that captures both the overall tumor kinetics and the individual cellular behavior. We track single cells as agents, cell density on a coarser scale, and growth factor diffusion and dynamics on a finer scale over time and space. Our model parameters were fit utilizing serial MRI imaging and cell tracking data from ex vivo tissue slices acquired from a growth-factor driven glioblastoma murine model. When fitting our model to serial imaging only, there was a spectrum of equally-good parameter fits corresponding to a wide range of phenotypic behaviors. When fitting our model using imaging and cell scale data, we determined that environmental heterogeneity alone is insufficient to match the single cell data, and intrinsic heterogeneity is required to fully capture the migration behavior. The wide spectrum of in silico tumors also had a wide variety of responses to an application of an anti-proliferative treatment. Recurrent tumors were generally less proliferative than pre-treatment tumors as measured via the model simulations and validated from human GBM patient histology. Further, we found that all tumors continued to grow with an anti-migratory treatment alone, but the anti-proliferative/anti-migratory combination generally showed improvement over an anti-proliferative treatment alone. Together our results emphasize the need to better understand the underlying phenotypes and tumor heterogeneity present in a tumor when designing therapeutic regimens.

Project description:BackgroundThe presence of semen in the vagina from unprotected sex may influence the immune and microbial environment of the female genital tract. Inflammatory cytokine concentrations and BV-associated bacteria in female genital secretions may influence HIV risk, although the effect of recent sexual intercourse on incident BV and the cytokine milieu of cervicovaginal secretions has rarely been measured in previous studies. Here, we investigated the extent to which partner semen impacts the cytokine response and incident BV.MethodsAt baseline, we assessed the recency of semen exposure in menstrual cup supernatants by quantifying prostate specific antigen (PSA) levels using ELISA in 248 HIV-uninfected women at high risk for HIV infection. Luminex was used to measure 48 cytokines in menstrual cup supernatants and vaginal swabs to diagnose BV by Nugent score. Point-of-care screening for Chlamydia trachomatis and Neisseria gonorrhoeae was conducted using GeneXpert while OSOM was used for Trichomonas vaginalis detection. Multivariable models, adjusted for age, sexually transmitted infections, BV, current contraception use and condom use, were used to assess the impact of semen exposure on biomarkers of inflammation and BV.ResultsPresence of PSA, indicating recent semen exposure within 48 hours prior to sampling, was observed in menstrual cup supernatants of 17% (43/248) of women. Of these women, 70% (30/43) had self-reported condom use at their last sex act and 84% (36/43) had BV (Nugent score >7). PSA presence was significantly associated with prevalent BV (Relative Risk (RR), 2.609; 95% Confidence Interval (CI), 1.104 - 6.165; p = 0.029). Furthermore, women with detectable PSA had high median concentrations of macrophage inflammatory protein- beta (MIP-1α, p=0.047) and low median concentration of the stem cell growth factor beta (SCGF-β, p=0.038) compared to those without PSA.ConclusionA degree of discordance between self-reports of consistent condom use and PSA positivity was observed. There was also evidence of a relationship between recent semen exposure, BV prevalence and altered cytokine concentrations. These findings suggest that PSA, as a semen biomarker, should be taken into consideration when investigating biological markers in the female genital tract and self-reported condom use in studies on reproductive and sexual health.

Dataset Information

Tissue-Specific Distribution of iNKT Cells Impacts Their Cytokine Response.

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Tissue-Specific Distribution of iNKT Cells Impacts Their Cytokine Response.

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