Inflammatory cytokines as a third signal for T cell activation

Center for Immunology, Department of Laboratory Medicine & Pathology, University of Minnesota, Minneapolis, MN 55455, USA.
Current opinion in immunology (Impact Factor: 7.48). 04/2010; 22(3):333-40. DOI: 10.1016/j.coi.2010.02.013
Source: PubMed


CD8 T cells require a third signal, along with Ag and costimulation, to make a productive response and avoid death and/or tolerance induction. Recent studies indicate that IL-12 and Type I IFN (IFNalpha/beta) are the major sources of signal 3 in a variety of responses, and that the two cytokines stimulate a common regulatory program involving altered expression of about 350 genes. Signal 3-driven chromatin remodeling is likely to play a major role in this regulation. Although less well studied, there is emerging evidence that CD4 T cells may also require a 'third signal' for a productive response and that IL-1 can provide this signal. Signal 3 cytokines can replace adjuvants in supporting in vivo T cell responses to peptide and protein antigens, and a better understanding of their activities and mechanisms should contribute to more rational design of vaccines.

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    • "Mature DCs are well known to provide costimulatory signals that initiate development of naive CD8 + T cells into functional cytotoxic effector T cells (Zhang and Bevan, 2011). In particular, certain stimulatory cytokines like interferons and IL-12 are crucial for the acquisition of T cell effector function like GzmB expression and IFNg production (Curtsinger and Mescher, 2010). This developmental process takes at least 48 hr and correlates with T cell proliferation (Curtsinger et al., 2005a; van Stipdonk et al., 2001). "
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    ABSTRACT: Immune control of infections with viruses or intracellular bacteria relies on cytotoxic CD8(+) T cells that use granzyme B (GzmB) for elimination of infected cells. During inflammation, mature antigen-presenting dendritic cells instruct naive T cells within lymphoid organs to develop into effector T cells. Here, we report a mechanistically distinct and more rapid process of effector T cell development occurring within 18 hr. Such rapid acquisition of effector T cell function occurred through cross-presenting liver sinusoidal endothelial cells (LSECs) in the absence of innate immune stimulation and known costimulatory signaling. Rather, interleukin-6 (IL-6) trans-signaling was required and sufficient for rapid induction of GzmB expression in CD8(+) T cells. Such LSEC-stimulated GzmB-expressing CD8(+) T cells further responded to inflammatory cytokines, eliciting increased and protracted effector functions. Our findings identify a role for IL-6 trans-signaling in rapid generation of effector function in CD8(+) T cells that may be beneficial for vaccination strategies.
    Cell Reports 09/2014; 8(5). DOI:10.1016/j.celrep.2014.07.008 · 8.36 Impact Factor
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    • "Initial studies suggesting that cytokines, particularly IL-12, may be important for signaling directly to T cells were made in in vitro cultures of T cells and artificial APCs more than a decade ago. Since then, the importance of IL-12 and type I interferon signaling directly to CD8 T cells for optimal effector cell accumulation has been demonstrated both in vitro and in vivo (3–7). Despite the clear impact of IL-12 and IFNα/β on effector CD8 T cell numbers, it remained unclear how inflammatory cytokines regulated the magnitude of effector CD8 T cell responses. "
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    ABSTRACT: Inflammatory cytokines have long been recognized to produce potent APCs to elicit robust T cell responses for protective immunity. The impact of inflammatory cytokine signaling directly on T cells, however, has only recently been appreciated. Although much remains to be learned, the CD8 T cell field has made considerable strides in understanding the effects of inflammatory cytokines throughout the CD8 T cell response. Key findings first identified IL-12 and type I interferons as "signal 3" cytokines, emphasizing their importance in generating optimal CD8 T cell responses. Separate investigations revealed another inflammatory cytokine, IL-15, to play a critical role in memory CD8 T cell maintenance. These early studies highlighted potential regulators of CD8 T cells, but were unable to provide mechanistic insight into how these inflammatory cytokines enhanced CD8 T cell-mediated immunity. Here, we describe the mechanistic advances that have been made in our lab regarding the role of "signal 3" cytokines and IL-15 in optimizing effector and memory CD8 T cell number and function. Furthermore, we assess initial progress on the role of cytokines, such as TGF-β, in generation of recently described resident memory CD8 T cell populations.
    Frontiers in Immunology 06/2014; 5:295. DOI:10.3389/fimmu.2014.00295
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    • "In recent times, the third signal in the form of inflammatory cytokines has been recognized for the activation of both CD4 and CD8 T cells (43, 44). Cumulative evidence demonstrates that IFN-α/β and IL-12 are required as the third signal for the functional activation of CD8 T cells (43, 45, 46), and that the absence of these cytokines results in the development of defective CD8 T primary and memory responses (47). "
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    ABSTRACT: Anti-tumor immunity can eliminate existing cancer cells and also maintain a constant surveillance against possible relapse. Such an antigen-specific adaptive response begins when tumor-specific T cells become activated. T-cell activation requires two signals on antigen presenting cells (APCs): antigen presentation through major histocombatibility complex (MHC) molecules and co-stimulation. In the absence of one or both these signals, T cells remain inactivated or can even become tolerized. Cancer cells and their associated microenvironment strategically hinder the processing and presentation of tumor antigens and consequently prevent the development of anti-tumor immunity. Many studies, however, demonstrate that interventions that over-turn tumor-associated immune evasion mechanisms can establish anti-tumor immune responses of therapeutic potential. One such intervention is oncolytic virus (OV)-based anti-cancer therapy. Here, we discuss how OV-induced immunological events override tumor-associated antigen presentation impairment and promote appropriate T cell-APC interaction. Detailed understanding of this phenomenon is pivotal for devising the strategies that will enhance the efficacy of OV-based anti-cancer therapy by complementing its inherent oncolytic activities with desired anti-tumor immune responses.
    Frontiers in Oncology 04/2014; 4:77. DOI:10.3389/fonc.2014.00077
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