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: 7.87). 04/2010; 22(3):333-40. DOI: 10.1016/j.coi.2010.02.013
Source: PubMed

ABSTRACT 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 · 7.21 Impact Factor
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    • "The detection of presented antigen is not sufficient to fully activate naı¨ve CD8 T cells as they sense the infection for the first time. Instead, the response is restrained until the cells receive additional cell–cell contact dependent costimulatory signals, and inflammatory warning signs which are delivered in the form of specific cytokines induced by the infection (Cox et al., 2011; Curtsinger and Mescher, 2010). These activatory checkpoints prevent illegitimate triggering of naive CD8 T cells, but also permit swift and overwhelming responses to the immunological disequilibrium caused by infection. "
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    ABSTRACT: Viral infections cause an immunological disequilibrium that provokes CD8 T cell responses. These cells play critical roles in purging acute infections, limiting persistent infections, and conferring life-long protective immunity. At every stage of the response anti-viral CD8 T cells are sensitive to signals from cytokines. Initially cytokines operate as immunological warning signs that inform of the presence of an infection, and also influence the developmental choices of the responding cells. Later during the course of the response other sets of cytokines support the survival and maintenance of the differentiated anti-viral CD8 T cells. Although many cytokines promote virus-specific CD8 T cells, other cytokines can suppress their activities and thus favor viral persistence. In this review we discuss how select cytokines act to regulate anti-viral CD8 T cells throughout the response and influence the outcome of viral infections.
    Virology 01/2013; 435(1):157-169. DOI:10.1016/j.virol.2012.09.012 · 3.28 Impact Factor
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    • "In addition to encounter with specific peptide/MHC molecules and costimulation (in the form of B7 or other ligands), the inflammatory environment surrounding the cell also has a large impact on the development of memory populations. IL-12 and IFN-α/β are well-defined for providing a " Signal 3, " and promote optimal development of both effector and memory cell populations (Mescher et al., 2006; Curtsinger and Mescher, 2010), although the specific cytokine may impact the characteristics of the resulting effector and memory pool. Signal 3 cytokines regulate an impressive number of gene expression changes (including those encoding factors that regulate survival, effector function, and trafficking) and chromatin remodeling may also be an important action of Signal 3 cytokines in CD8 T cells (Agarwal et al., 2009). "
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    ABSTRACT: Understanding the mechanisms that regulate the differentiation and maintenance of CD8(+) memory T cells is fundamental to the development of effective T cell-based vaccines. Memory cell differentiation is influenced by the cytokines that accompany T cell priming, the history of previous antigen encounters, and the tissue sites into which memory cells migrate. These cues combine to influence the developing CD8(+) memory pool, and recent work has revealed the importance of multiple transcription factors, metabolic molecules, and surface receptors in revealing the type of memory cell that is generated. Paired with increasingly meticulous subsetting and sorting of memory populations, we now know the CD8(+) memory pool to be phenotypically and functionally heterogeneous in nature. This includes both recirculating and tissue-resident memory populations, and cells with varying degrees of inherent longevity and protective function. These data point to the importance of tailored vaccine design. Here we discuss how the diversity of the memory CD8(+) T cell pool challenges the notion that "one size fits all" for pathogen control, and how distinct memory subsets may be suited for distinct aspects of protective immunity.
    Frontiers in Immunology 11/2012; 3:353. DOI:10.3389/fimmu.2012.00353
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