Cytokine-induced differentiation of precursor mouse CD8+ T cells into cytotoxic CD8+ T cells secreting Th1 or Th2 cytokines

Sad, Subash; Marcotte, Rita; Mosmann, Tim R.

doi:10.1016/1074-7613(95)90051-9

Cited by 635 publications

(398 citation statements)

References 49 publications

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“…Some studies have shown that IL-4-induced CD8 + Tc2 cells still remain, sometimes even have increased cytotoxicity (37)(38)(39)(40). So, the effects of IL-4 on CD8 + T cells may rely on the initial cell status, the presence of other cytokines and the stimulating methods.…”

Section: Endogenous Il-4 Deviates Host Immune Response To An Ineffectmentioning

confidence: 99%

Paradoxical Roles of IL-4 in Tumor Immunity

2009

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Section: Endogenous Il-4 Deviates Host Immune Response To An Ineffectmentioning

confidence: 99%

Paradoxical Roles of IL-4 in Tumor Immunity

2009

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“…1). Contaminating Tc1 cells are invariably found in Tc2 preparations [6,7,11,19]. In all our test conditions, approximately 25% of IFN-cproducing cells were present in the Tc2 cultures (Fig.…”

Section: Resultsmentioning

confidence: 64%

“…The cytolytic activity of Tc2 cells is under discussion. Whereas some investigators have reported on non-cytolytic Tc2 cells [51], others have shown similar [6,19,52] and even slightly higher cytotoxic potential for Tc2 cells [11]. The different results may be, at least in part, due to the purity of the different Tc2 cell preparations.…”

Section: Discussionmentioning

confidence: 97%

“…IL-12 also appears to be critical for the generation of Tc1 cells, characterized by a high production level of IFN-c and cytolytic activity, CC chemokine receptor (CCR)5 expression and the ability to migrate to the inflamed tissues where they are highly efficient in eliminating viral infections and tumor cells. IL-4 [4][5][6] and TGF-b [7,8] are critical for the polarization of Tc2 cells, mainly characterized by IL-4, IL-5, IL-10 and TGF-b production [4,6,9,10], CCR4 expression, and a reduced capacity to migrate to the inflamed tissues [11].…”

Section: Introductionmentioning

confidence: 99%

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Prolonged exposure of dendritic cells to maturation stimuli favors the induction of type‐2 cytotoxic T lymphocytes

Boni¹,

Iezzi

Degl’Innocenti³

et al. 2006

Eur J Immunol

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Dendritic cell (DC) maturation influences the priming and polarization of T lymphocytes. We recently found that early activated DC (i.e. DC exposed to promaturation stimuli for 8 h) were more prone to prime in vivo a type-1 cytotoxic T cell (Tc1) response than DC exposed to pro-maturation stimuli for 48 h (48h-DC). We investigated whether 48h-DC, conversely, allowed the induction of Tc2 cells. Antigenpulsed mouse bone-marrow-derived DC at any maturation stage, in the presence of exogenous IL-12, skewed in vitro naive CD8 + T cells towards Tc1 cells, but 48h-DC most potently, in the presence of exogenous IL-4, favored the induction of Tc2 cells. In vivo, full maturation of DC promoted expansion of Tc2 and fall of Tc1 cells. Tc2 cells maintained a high cytolytic activity and produced significant amounts of IL-4, IL-5, IL-10 and TGF-b. Our results indicate that polarization of naive CD8 + T cells to Tc2 cells is dependent on the amount of time DC have been exposed to maturation stimuli, and might be favored in late and/or chronic phases of an immune response.Supporting information for this article is available at http://www.wiley-vch.de/contents/jc_2040/2006/35597_s.pdf IntroductionUpon antigenic stimulation, T lymphocytes proliferate and acquire a variety of effector functions. Indeed, activation of naive CD4 + T cells in the presence of IL-12 results in the development of Th1 cells, which mainly secrete interferon (IFN)-c, interleukin (IL)-2, tumor necrosis factor (TNF)-a and lymphotoxin, and are commonly associated with a cell-mediated immune response. Conversely, the presence of IL-4 skews the Th response towards Th2 cells producing IL-4, IL-10 and IL-13, relevant cytokines against helminthiasis and allergic diseases [1]. More recently, a third subset of CD4 + T cells has been identified, which express CD25, produce IL-10 and TGF-b, and display regulatory functions [2].The polarization of CD8 + CTL has been less characterized [3]. IL-12 also appears to be critical for the generation of Tc1 cells, characterized by a high production level of IFN-c and cytolytic activity, CC chemokine receptor (CCR)5 expression and the ability to migrate to the inflamed tissues where they are [16], and in many cases their presence was associated with disease severity and progression [13][14][15][16]. In mouse tumor models, IL-4-transduced tumor cells elicited potent antitumor activities [17] and induced Tc2 cells able to cure lung metastases [5,17]. IL-4 produced by CTL was required for the generation of protective tumor-associated CD8 + T cells [5,18]. In other models, Tc2 cells were far less effective in curing subcutaneous tumors [19,20] and lung metastases [21]. Finally, CD8 + T cell subpopulations exhibiting regulatory function have also been described [14,22].Dendritic cells (DC), professional antigen presenting cells (APC) with a unique ability in priming T cell responses [23], play a key role in T cell polarization. In particular, it has been reported that subsets of DC, derived from distinct precursors, induce differenti...

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“…26,27 IFNg is generally made and secreted by activated T and NK lymphocytes. [28][29][30] It mediates many immune functions, and is important in activating cytotoxic responses against virus-infected cells. IFNg also possesses antiviral activities that are mechanistically similar HCV-activated conditional expression vectors AA Matskevich and DS Strayer to those described for IFNa and IFNb.…”

Section: Discussionmentioning

confidence: 99%

Exploiting hepatitis C virus activation of NFκB to deliver HCV-responsive expression of interferons α and γ

Matskevich

Strayer

2003

Gene Ther

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hronic infection with hepatitis C virus (HCV) may lead to liver failure and hepatocellular carcinoma. Current treatment for HCV includes high systemic doses of interferona (IFNa), which is effective in less than half of patients and may have severe side effects. We designed conditional IFNa and IFNg expression constructs to be triggered by HCV-induced activation of NFkB, and delivered these using highly efficient recombinant Tag-deleted SV40-derived vectors. NFkB activates the HIV-1NL4-3 long terminal repeat (HIVLTR) as a promoter, which accounts for the conditional transgene expression. Human hepatocyte lines and primary rat hepatocytes (PRH) were transduced with SV[HIVLTR](IFN) vectors, and transfected with HCV cDNA. Production of human and murine IFNa and IFNg in cytosol and culture supernatants was measured. HCV activated the HIVLTR to produce and secrete IFNs, and did so largely through the NFkB binding sites of the HIVLTR. Levels of IFNs secreted, and the magnitude of induction in response to HCV, were greater in hepatocyte lines than in primary cultured hepatocytes. However, even in the latter, supernatant IFNa concentrations achieved by this approach were similar to therapeutic serum concentrations sought in systemic IFNatreated patients. In coculture studies, secreted IFNa activated its cognate response elements in untransduced cells, suggesting that its potential inhibitory effects on HCV may not be limited to transduced cells. Although HCV replication in culture is difficult to assess, HCV-induced IFNa production demonstrably reduced HCV transcription. Conditional expression of IFNs within the liver may represent an attractive approach to therapy of severe chronic HCV infection that could avoid the side effects of systemic treatment regimens.

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Cytokine-induced differentiation of precursor mouse CD8+ T cells into cytotoxic CD8+ T cells secreting Th1 or Th2 cytokines

Cited by 635 publications

References 49 publications

Paradoxical Roles of IL-4 in Tumor Immunity

Paradoxical Roles of IL-4 in Tumor Immunity

Prolonged exposure of dendritic cells to maturation stimuli favors the induction of type‐2 cytotoxic T lymphocytes

Exploiting hepatitis C virus activation of NFκB to deliver HCV-responsive expression of interferons α and γ

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