T cell cytokines are known to play a major role in determining protection and pathology in infectious disease. It has recently become clear that IL-12 is a key inducer of the type 1 T cell cytokine pattern characterized by production of IFN-␥ . Conversely, IL-10 down-regulates IL-12 production and type 1 cytokine responses. We have investigated whether IL-12 and IL-10 might be involved in a chronic inflammatory reaction, atherosclerosis. In atherosclerotic plaques, we found strong expression of IFN-␥ but not IL-4 mRNAs as compared to normal arteries. IL-12 p40 mRNA and IL-12 p70 protein were also found to be abundant in atherosclerotic plaques. IL-12 was induced in monocytes in vitro in response to highly oxidized LDL but not minimally modified LDL. The cross-regulatory role of IL-10 was indicated by the expression of IL-10 in some atherosclerotic lesions, and the demonstration that exogenous rIL-10 inhibited LDL-induced IL-12 release. These data suggest that the balance between IL-12 and IL-10 production contributes to the level of immune-mediated tissue injury in atherosclerosis. (
Determining the magnitude and kinetics, together with the phenotypic and functional characteristics of responding CD8 T cells, is critical for understanding the regulation of adaptive immunity as well as in evaluating vaccine candidates. Recent technical advances have allowed tracking of some CD8 T cells responding to infection, and a body of information now exists describing phenotypic changes that occur in CD8 T cells of known Ag-specificity during their activation, expansion, and memory generation in inbred mice. In this study, we demonstrate that Ag but not inflammation-driven changes in expression of CD11a and CD8α can be used to distinguish naive from Ag-experienced (effector and memory) CD8 T cells after infection or vaccination. Interestingly and in contrast to inbred mice, tracking polyclonal CD8 T cell responses with this approach after bacterial and viral infections revealed substantial discordance in the magnitude and kinetics of CD8 T cell responses in outbred hosts. These data reveal limitations to the use of inbred mouse strains as preclinical models at vaccine development and suggest the same dose of infection or vaccination can lead to substantial differences in the magnitude and timing of Ag-specific CD8 expansion as well in differences in protective memory CD8 T cell numbers in outbred individuals. This concept has direct relevance to development of vaccines in outbred humans.
Inflammatory cytokines induced by infection or vaccination with adjuvant act directly or indirectly on CD8 T cells to modulate their expansion, contraction, and acquisition of memory characteristics. Importantly, the initial exposure of naive T cells to inflammatory cytokines may occur before, during, or after their interaction with stimulating dendritic cells (DC) and it is unknown whether and how the timing of cytokine exposure impacts the CD8 T cell response. In this study, we use an immunization strategy with peptide-coated mature DC that, in the absence of inflammatory cytokines, results in a transient effector phase followed by the accelerated acquisition of memory characteristics by the responding CD8 T cells. Induction of inflammatory cytokines by TLR agonists, at the time of DC immunization or 2–4 days after DC immunization, prevented the early acquisition of memory characteristics by the responding CD8 T cells. Interestingly, although induction of inflammatory cytokines at the time of DC immunization increased the effector response, induction of inflammatory cytokines after DC immunization did not promote further expansion of the responding CD8 T cells but still prevented their early acquisition of memory characteristics. In contrast, induction of inflammatory cytokines 2 days before DC immunization did not prevent the CD8 T cells from early acquisition of memory characteristics. Furthermore, TLR ligand-induced inflammatory cytokines had the most significant impact on the phenotype and function of proliferating CD8 T cells. These data suggest that a default pathway of memory CD8 T cell differentiation is deflected toward sustained effector commitment by encounter with inflammatory cytokines during Ag-driven proliferation.
Antigen presentation by mature dendritic cells (DCs) is the first step for initiating adaptive immune responses. DCs are composed of heterogeneous functional subsets; however, the molecular mechanisms that regulate differentiation of specific DC subsets are not understood. Here, we report that the basic leucine zipper transcription factor NFIL3/E4BP4 is essential for the development of CD8␣ ؉ conventional DCs (cDCs). Nfil3 ؊/؊ mice specifically lack CD8␣ ؉ cDCs but not CD8␣ ؊ cDCs or plasmacytoid DCs in lymphoid tissues. Flt3 ligand-dependent generation of CD8␣ ؉ cDCs in lymphoid tissues and CD8␣ ؉ -equivalent cDCs from Nfil3 ؊/؊ bone marrow cells was also impaired. NFIL3 regulates CD8␣ ؉ cDC development in part through Batf3 expression. Importantly, Nfil3 ؊/؊ mice exhibited impaired cross-priming of CD8 ؉ T cells against cellassociated antigen, a process normally performed by CD8␣ ؉ cDCs, and failed to produce IL-12 after TLR3 stimulation. IntroductionDendritic cells (DCs) are effective antigen-presenting cells that both initiate antigen-specific immune responses and generate and maintain self-tolerance. 1 DCs can develop from bone marrow (BM) progenitor cells and reside in the peripheral lymphoid tissues. Several DC subsets were identified by their cell-surface phenotypes, residential location, and functional differences. 2 Splenic DCs are divided into 2 major populations: plasmacytoid DCs (pDCs) and conventional DCs (cDCs). The cDCs are further divided into CD8␣ ϩ and CD8␣ Ϫ DCs. CD8␣ ϩ DCs predominantly produce IL-12 in response to microbial antigens, tumor cells, and virus-infected cells. 1-3 Importantly, CD8␣ ϩ DCs are specialized cells for the cross-presentation of antigens by MHC class I molecules. 4,5 Analyses of mice lacking transcription factor genes such as Irf4, Irf8, and Batf3 revealed their essential roles in the development of distinct subsets of DCs. [6][7][8][9] NFIL3 (nuclear factor, IL-3 regulated; also called E4BP4) was originally identified as an adenovirus E4 promoter-and human IL3 gene promoter-binding protein, and its role in circadian regulation has been well studied. [10][11][12] However, the role of NFIL3 in the immune system was not largely elucidated until Nfil3 Ϫ/Ϫ mice were established recently. We have demonstrated that Nfil3 Ϫ/Ϫ mice have defects in IgE class switching by regulating Ig-⑀ germline transcription in B cells. 13 Nfil3 Ϫ/Ϫ mice also lack natural killer (NK) cells, which suggests a role for NFIL3 in NK cell development. [13][14][15] Here, we demonstrate impaired CD8␣ ϩ DC development and impaired cross-priming activity of CD8 ϩ T cells in response to cell-mediated antigen in Nfil3 Ϫ/Ϫ mice. Our results provide compelling evidence that NFIL3 is a key regulator of CD8␣ ϩ DC development. Methods MiceNfil3 Ϫ/Ϫ mice 13 (C57BL/6 background) were used for all experiments. All experimental mouse protocols were approved by the Institutional Animal Care and Use Committee of University of Iowa. Real-time RT-PCRcDNA was prepared from RNA isolated from cells by the SuperScript Fi...
Tim-3 is a surface molecule expressed throughout the immune system that can mediate both stimulatory and inhibitory effects. Previous studies have provided evidence that Tim-3 functions to enforce CD8 T cell exhaustion, a dysfunctional state associated with chronic stimulation. In contrast, the role of Tim-3 in the regulation of CD8 T cell responses to acute and transient stimulation remains undefined. To address this knowledge gap, we examined how Tim-3 affects CD8 T cell responses to acute Listeria monocytogenes (LM) infection. Analysis of wild-type (WT) mice infected with LM revealed that Tim-3 was transiently expressed by activated CD8 T cells and was associated primarily with acquisition of an effector phenotype. Comparison of responses to LM by WT and Tim-3 KO mice showed that the absence of Tim-3 significantly reduced the magnitudes of both primary and secondary CD8 T cell responses, which correlated with decreased IFN-γ production and degranulation by Tim-3 KO cells stimulated with peptide antigen ex vivo. To address the T cell-intrinsic role of Tim-3, we analyzed responses to LM infection by WT and Tim-3 KO TCR-transgenic CD8 T cells following adoptive transfer into a shared WT host. In this setting, the accumulation of CD8 T cells and the generation of cytokine-producing cells were significantly reduced by the lack of Tim-3, demonstrating that this molecule has a direct effect on CD8 T cell function. Combined, our results suggest that Tim-3 can mediate a stimulatory effect on CD8 T cell responses to an acute infection.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2025 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.