Responsiveness of Naive CD4 T Cells to Polarizing Cytokine Determines the Ratio of Th1 and Th2 Cell Differentiation

Mikhalkevich, Natallia; Becknell, Brian; Caligiuri, Michael A.; Bates, Michael D.; Harvey, Richard P.; Zheng, Weiping

doi:10.4049/jimmunol.176.3.1553

Cited by 35 publications

(29 citation statements)

References 50 publications

(51 reference statements)

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“…The dichotomy of type 1 and type 2 cells stands as a central paradigm that provides the framework to understand the nature of an immune response that is either beneficial or detrimental to the host (34,52). Our data showed that uptake of a larger number of R. conorii correlated with a higher level of IL-12p40 production in B6 BMDCs compared to those of C3H counterparts (Fig.…”

Section: Discussionsupporting

confidence: 57%

Differential Interaction of Dendritic Cells withRickettsia conorii: Impact on Host Susceptibility to Murine Spotted Fever Rickettsiosis

Fang¹,

Ismail²,

Soong

et al. 2007

Infect Immun

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Spotted fever group rickettsioses are emerging and reemerging infectious diseases, some of which are life-threatening. In order to understand how dendritic cells (DCs) contribute to the host resistance or susceptibility to rickettsial diseases, we first characterized the in vitro interaction of rickettsiae with bone marrow-derived DCs (BMDCs) from resistant C57BL/6 (B6) and susceptible C3H/HeN (C3H) mice. In contrast to the exclusively cytosolic localization within endothelial cells, rickettsiae efficiently entered and localized in both phagosomes and cytosol of BMDCs from both mouse strains. Rickettsia conorii-infected BMDCs from resistant mice harbored higher bacterial loads compared to C3H mice. R. conorii infection induced maturation of BMDCs from both mouse strains as judged by upregulated expression of classical major histocompatibility complex (MHC) and costimulatory molecules. Compared to C3H counterparts, B6 BMDCs exhibited higher expression levels of MHC class II and higher interleukin-12 (IL-12) p40 production upon rickettsial infection and were more potent in priming naïve CD4؉ T cells to produce gamma interferon. In vitro DC infection and T-cell priming studies suggested a delayed CD4 ؉ T-cell activation and suppressed Th1/Th2 cell development in C3H mice. The suppressive CD4؉ T-cell responses seen in C3H mice were associated with a high frequency of Foxp3 ؉ T regulatory cells promoted by syngeneic R. conorii-infected BMDCs in the presence of IL-2. These data suggest that rickettsiae can target DCs to stimulate a protective type 1 response in resistant hosts but suppressive adaptive immunity in susceptible hosts.

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Section: Discussionsupporting

confidence: 57%

Differential Interaction of Dendritic Cells withRickettsia conorii: Impact on Host Susceptibility to Murine Spotted Fever Rickettsiosis

Fang¹,

Ismail²,

Soong

et al. 2007

Infect Immun

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“…All animal studies were performed in compliance to rules stipulated in the policies of the University of Rochester Committee on Animal Research. As previously described (18,37), for Th1 and Th2 cell differentiation, CD4 T cells were stimulated with OVA 223-239 peptide (0.5 g/ml) or ConA (Sigma-Aldrich) (2.5 g/ml) plus T cell-deleted spleen cells as APC and 50 U/ml human IL-2 (Roche). For Th1 differentiation, the cultures were supplemented with IL-12 (Biogen) (5 ng/ml) and anti-IL-4 Abs (11B11) (BD Pharmingen) (1 g/ml), whereas for Th2 differentiation, the cultures were supplemented with IL-4 (BD Pharmingen) (10 ng/ml), anti-IFN-␥ (XMG1.2) and anti-IL-12 Abs (BD Pharmingen) (1 g/ml).…”

Section: Do1110camentioning

confidence: 99%

Interaction between GATA-3 and the Transcriptional Coregulator Pias1 Is Important for the Regulation of Th2 Immune Responses

Zhao¹,

Zheng²,

Huang³

et al. 2007

The Journal of Immunology

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Th2 cytokine expression is dependent on the transcription factor GATA-3. However, the molecular interactions of GATA-3 leading to Th2 cytokine gene activation have not been well characterized. Here, we reported a number of GATA-3 associated proteins in Th2 cells, and one of such proteins Pias1 functioned as a positive transcriptional coregulator for GATA-3. When overexpressed in Th2 cells, Pias1 enhanced the expression of IL-13, and to lesser degrees, IL-4 and -5. Conversely, Pias1 siRNA down-regulated the Th2 cytokine expression. In Leishmania major infection, manipulating Pias1 expression in parasite-reactive CD4 T cells altered severity of disease caused by Th2 responses. Mechanistically, Pias1 markedly potentiated GATA-3-mediated activation of the IL-13 promoter by facilitating the recruitment of GATA-3 to the promoter. In contrast, IL-5 promoter was modestly enhanced by Pias1 and no effect was observed on IL-4 promoter. Thus, both promoter activation and additional mechanisms are responsible for regulation by Pias1.

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“…Because IL-4 is required for normal T H 2 differentiation, Hlx deficiency results in impaired production of T H 2 cytokines, and this phenotype can be reversed by ectopic retroviral expression of IL-4R␣. 34 Apart from promoting T H 2 differentiation, IL-4 is a potent inhibitor of IFN-␥ production by T cells. 35 Therefore, by decreasing the responsiveness of a CD4 ϩ T cell to IL-4 during early T H 2 polarization, Hlx may indirectly promote the production of IFN-␥ by this lymphocyte population.…”

Section: Discussionmentioning

confidence: 99%

Hlx homeobox transcription factor negatively regulates interferon-γ production in monokine-activated natural killer cells

Becknell¹,

Hughes

Freud³

et al. 2006

Blood

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Natural killer (NK) cells contribute to host immunity, including tumor surveillance, through the production of interferon gamma (IFN-γ). Although there is some knowledge about molecular mechanisms that induce IFN-γ in NK cells, considerably less is known about the mechanisms that reduce its expression. Here, we investigate the role of the Hlx transcription factor in IFN-γ production by NK cells. Hlx expression is induced in monokine-activated NK cells, but with delayed kinetics compared to IFN-γ. Ectopic Hlx expression decreases IFN-γ synthesis in primary human NK cells and IFN-γ promoter activity in an NK-like cell line. Hlx protein levels inversely correlate with those of STAT4, a requisite factor for optimal IFN-γ transcription. Mechanistically, we provide evidence indicating that Hlx overexpression accelerates dephosphorylation and proteasome-dependent degradation of the active Y693-phosphorylated form of STAT4. Thus, Hlx expression in activated NK cells temporally controls and limits the monokine-induced production of IFN-γ, in part through the targeted depletion of STAT4.

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Responsiveness of Naive CD4 T Cells to Polarizing Cytokine Determines the Ratio of Th1 and Th2 Cell Differentiation

Cited by 35 publications

References 50 publications

Differential Interaction of Dendritic Cells withRickettsia conorii: Impact on Host Susceptibility to Murine Spotted Fever Rickettsiosis

Differential Interaction of Dendritic Cells withRickettsia conorii: Impact on Host Susceptibility to Murine Spotted Fever Rickettsiosis

Interaction between GATA-3 and the Transcriptional Coregulator Pias1 Is Important for the Regulation of Th2 Immune Responses

Hlx homeobox transcription factor negatively regulates interferon-γ production in monokine-activated natural killer cells

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