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Programming of Distinct Chemokine-Dependent and -Independent Search Strategies for Th1 and Th2 Cells Optimizes Function at Inflamed Sites.

ABSTRACT: T-helper (Th) cell differentiation drives specialized gene programs that dictate effector T cell function at sites of infection. Here, we have shown Th cell differentiation also imposes discrete motility gene programs that shape Th1 and Th2 cell navigation of the inflamed dermis. Th1 cells scanned a smaller tissue area in a G protein-coupled receptor (GPCR) and chemokine-dependent fashion, while Th2 cells scanned a larger tissue area independent of GPCR signals. Differential chemokine reliance for interstitial migration was linked to STAT6 transcription-factor-dependent programming of integrin ?V?3 expression: Th2 cell differentiation led to high ?V?3 expression relative to Th1 cells. Th1 and Th2 cell modes of motility could be switched simply by manipulating the amount of ?V?3 on the cell surface. Deviating motility modes from those established during differentiation impaired effector function. Thus, programmed expression of ?V?3 tunes effector T cell reliance on environmental cues for optimal exploration of inflamed tissues.

SUBMITTER: Gaylo-Moynihan A

PROVIDER: S-EPMC6904228 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Programming of Distinct Chemokine-Dependent and -Independent Search Strategies for Th1 and Th2 Cells Optimizes Function at Inflamed Sites.

Gaylo-Moynihan Alison A Prizant Hen H Popović Milan M Fernandes Ninoshka R J NRJ Anderson Christopher S CS Chiou Kevin K KK Bell Hannah H Schrock Dillon C DC Schumacher Justin J Capece Tara T Walling Brandon L BL Topham David J DJ Miller Jim J Smrcka Alan V AV Kim Minsoo M Hughson Angela A Fowell Deborah J DJ

Immunity 20190806 2

T-helper (Th) cell differentiation drives specialized gene programs that dictate effector T cell function at sites of infection. Here, we have shown Th cell differentiation also imposes discrete motility gene programs that shape Th1 and Th2 cell navigation of the inflamed dermis. Th1 cells scanned a smaller tissue area in a G protein-coupled receptor (GPCR) and chemokine-dependent fashion, while Th2 cells scanned a larger tissue area independent of GPCR signals. Differential chemokine reliance f ...[more]

PMID: 31399281

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Project description:Interleukin 4 (IL-4) plays a central role in the orchestration of Type 2 immunity. During T cell activation in the lymph node, IL-4 promotes Th2 differentiation and inhibits Th1 generation. In the inflamed tissue, IL-4 signals promote innate and adaptive Type-2 immune recruitment and effector function, positively amplifying the local Th2 response. In this study, we identify an additional negative regulatory role for IL-4 in limiting the recruitment of Th1 cells to inflamed tissues. To test IL-4 effects on inflammation subsequent to Th2 differentiation, we transiently blocked IL-4 during ongoing dermal inflammation (using anti-IL-4 mAb) and analyzed changes in gene expression. Neutralization of IL-4 led to the upregulation of a number of genes linked to Th1 trafficking, including CXCR3 chemokines, CCL5 and CCR5 and an associated increase in IFN?, Tbet and TNF? genes. These gene expression changes correlated with increased numbers of IFN?-producing CD4+ T cells in the inflamed dermis. Moreover, using an adoptive transfer approach to directly test the role of IL-4 in T cell trafficking to the inflamed tissues, we found IL-4 neutralization led to an early increase in Th1 cell recruitment to the inflamed dermis. These data support a model whereby IL-4 dampens Th1-chemokines at the site of inflammation limiting Th1 recruitment. To determine biological significance, we infected mice with Leishmania major, as pathogen clearance is highly dependent on IFN?-producing CD4+ T cells at the infection site. Short-term IL-4 blockade in established L. major infection led to a significant increase in the number of IFN?-producing CD4+ T cells in the infected ear dermis, with no change in the draining LN. Increased lymphocyte influx into the infected tissue correlated with a significant decrease in parasite number. Thus, independent of IL-4's role in the generation of immune effectors, IL-4 attenuates lymphocyte recruitment to the inflamed/infected dermis and limits pathogen clearance.

Project description:BackgroundPersistent peripheral CD4+T cell differentiation towards T helper (Th)2 rather than Th1 has been proved to be related to immunosuppression and poor prognosis in sepsis. However, it is unclear whether these circulating Th1 and Th2 subtype accumulations differed in septic populations of distinct infection sites and presented different associations with outcomes among patients with pulmonary versus nonpulmonary sepsis.MethodsFrom a secondary analysis of a prospective observational study, seventy-four previously immunocompetent patients with community-acquired severe sepsis within 24 hours upon onset were enrolled. Whole blood was collected on the admission day (D0), 3rd day (D3), and 7th day (D7). The patients were classified as pulmonary (n = 52) and nonpulmonary sepsis (n = 22). Circulating Th1 and Th2 populations were evaluated by flow cytometry, and clinical data related to disease severity and inflammatory response were collected. The associations of circulating Th1 and Th2 subset accumulations with distinct infection sites or outcomes within subgroups were explored.ResultsPatients with pulmonary sepsis held similar disease severity and 28-day mortality with those of nonpulmonary sepsis. Of note is the finding that circulating Th2 levels on D7 (P = 0.04) as well as Th2/Th1 on D3 (P = 0.01) and D7 (P = 0.04) were higher in the pulmonary sepsis compared with nonpulmonary sepsis while Th1 levels were lower on D0, D3, and D7 (P = 0.01, <0.01, and =0.05, respectively). Compared to 28-day survivors, higher Th2/Th1 driven by increased Th2 were observed among 28-day nonsurvivors on D3 and D7 in both groups. The association between circulatory Th2 populations or Th2/Th1 and 28-day death was detected in pulmonary sepsis (P < 0.05, HR > 1), rather than nonpulmonary sepsis.ConclusionsCirculating Th2 accumulation was more apparent among pulmonary sepsis while nonpulmonary sepsis was characterized with the hyperactive circulating Th1 subset among previously immunocompetent patients. This finding suggested that circulating Th1 and Th2 subset accumulations vary in septic subgroups with different infection sites.

Dataset Information

Programming of Distinct Chemokine-Dependent and -Independent Search Strategies for Th1 and Th2 Cells Optimizes Function at Inflamed Sites.

Publications

Programming of Distinct Chemokine-Dependent and -Independent Search Strategies for Th1 and Th2 Cells Optimizes Function at Inflamed Sites.

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