Hepatic expansion of a virus-specific regulatory CD8+ T cell population in chronic hepatitis C virus infection

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...

Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

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

Boni¹,

Iezzi

Degl’Innocenti³

et al. 2006

Kinetics of CD8⁺ effector T cell responses and induced CD4⁺ regulatory T cell responses during Friend retrovirus infection

Zelinskyy¹,

Kraft²,

Schimmer³

et al. 2006

120

Cytolytic CD8 + T cells are critical for the control of acute Friend virus (FV) infection yet they fail to completely eliminate the virus during chronic infection because they are functionally impaired by regulatory T cells (Treg). We performed a kinetic analysis of T cell responses during FV infection to determine when dysfunction of CD8 + T cells and suppressive activity of CD4 + regulatory T cells develops. At 1 week post infection, virusspecific CD8 + T cells with effector phenotype and cytolytic potential expanded. Peak expansion was found at 12 days post infection, correlating with peak viral loads. After 2 weeks when viral loads dropped, numbers of activated CD8 + T cells started to decline. However, a population of virus-specific CD8 + T cells with effector phenotype was still detectable subsequently, but these cells had lost their ability to produce granzymes and to degranulate cytotoxic molecules. Contemporaneous with the development of CD8 + T cell dysfunction, different CD4 + T cell populations expressing cell surface markers for Treg and the Treg-associated transcription factor Foxp3 expanded. Transfer as well as depletion experiments indicated that regulatory CD4 + cells developed during the second week of FV infection and subsequently suppressed CD8 + T cell functions, which was associated with impaired virus clearance.

Type I and III interferons enhance IL‐10R expression on human monocytes and macrophages, resulting in IL‐10‐mediated suppression of TLR‐induced IL‐12

Liu¹,

Janssen²,

Boonstra

2012

Currently, only about 30-50% of chronic hepatitis C virus (HCV) and hepatitis B virus (HBV) patients respond to IFN-based therapy. It has been suggested that IL-10 is involved in suppressing the activity of type I IFNs on antigen-presenting cells (APCs). However, the interaction between type I IFNs and IL-10 is still not clear. Here we report that IFN-α priming upregulated the expression of IL-10R1 on monocytes, and subsequently IL-10 induced a higher level of STAT3 phosphorylation in IFN-primed cells. This indicates that IFN-α increased the sensitivity of monocytes to IL-10, and as a result, TLR-induced IL-12p70 by IFN-pretreated cells was suppressed. Interestingly, both IFN-β and IL-29, a member of the type III IFN family, comparably sensitized monocytes and macrophages to IL-10 stimulation, indicating a general effect of IFN on the activity of IL-10 in APCs. In summary, we demonstrate that one of the consequences of priming human APCs with IFN is to promote the cells' sensitivity to IL-10, which leads to the inhibition of TLR-induced IL-12p70 production. Therefore, type I and III IFNs induce a suboptimal activation of immune cells. These findings are relevant for the development of strategies to further improve IFN-based therapy for patients with multiple sclerosis or viral hepatitis.