Mechanisms that modulate the generation of Th17 cells are incompletely understood. We report that the activation of CK2 by CD5 is essential for the efficient generation of Th17 cells in vitro and in vivo. The CD5-CK2 signaling pathway enhanced TCR induced activation of AKT and promoted the differentiation of Th17 cells by two independent mechanisms: inhibiting GSK3, and activating mTOR. Genetic ablation of the CD5-CK2 signaling pathway attenuated TCR induced AKT activation and consequently increased activity of GSK3 in Th17 cells. This resulted in Th17 cells being more sensitive to IFN-γ mediated inhibition. In the absence of CD5-CK2 signaling, we observed decreased activity of S6K and attenuated nuclear translocation of RORγt. These results reveal a novel and essential function of CD5-CK2 signaling pathway and GSK3-IFNγ axis in regulating Th differentiation and provide a possible means to dampen Th17 responses in autoimmune diseases.
Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionUpon infection, T-cell activation and differentiation are initiated through TCR engagement of peptide-MHC molecules on the surface of APCs in the context of co-stimulation and inflammatory cytokines. These cues trigger numerous signal transduction cascades, whose integration is "translated" into changes in gene transcription, protein activity, and expression. This ultimately leads to the development of effector function and T-cell-mediated Correspondence: Dr. Mark A. Daniels e-mail: danielsma@missouri.edu immunity [1]. The MAPK SAPK/JNK cascade plays a major role in regulating a variety of fate decisions including activation, proliferation, differentiation, and death [2,3]. Three genes encode the JNK family members. JNK1 and JNK2 are ubiquitously expressed, whereas the expression of JNK3 is restricted to the brain, heart, and testis [2]. While each JNK isoform is ascribed a unique function, how activation of each is independently regulated is not well understood. Activation of JNK is important for shaping both the innate and adaptive immune response. For innate immune responses, the inflammatory cytokines TNF and IL-1 induce JNK activity [4]. JNK2 and IKKβ induce the production of proinflammatory cytokine response to viral dsRNA [5]. Inflammation-dependent activation of PLC-γ, JNK and NF-κB enhances the ability of DCs andwww.eji-journal.eu 3362 Cody A. Cunningham et al. Eur. J. Immunol. 2013. 43: 3361-3371 epithelium tissue to induce Th17 responses [6,7]. JNK signaling is implicated in regulating proinflammatory cytokine production, joint inflammation, and destruction in rheumatoid arthritis [8]. JNK is also required for polarization of proinflammatory macrophages, obesity-induced insulin resistance, and inflammation in adipose tissue [9]. For T lymphocytes, JNK activation plays different roles depending on the T-cell type, the maturation state, and the milieu of the responding cell [10]. For example, in developing thymocytes, JNK activation appears to have a role in negative selection and the induction of apoptosis [11,12] Together, these findings illustrate the extreme importance of JNK in an immune response and demonstrate the need to understand the specific regulation of JNK1 and JNK2 to control the outcome of these responses. The mechanisms that regulate the independent activation of the individual JNK isoforms are poorly understood. The functional specificity of a number of MAPK signaling pathways has been attributed to their regulation by scaffold molecules [20,21]. Scaffolds provide means for both spatial regulation and network formation that increase the number of outcomes possible when activating a given pathway [22] + T cells [27,28]. However, the scaffold proteins specific for TCR-mediated JNK1 activation is less clear. The TCR connects to JNK activation through the guanine exchange factor Vav1 and the adaptor/guanine exchange factor complex, Grb2/SOS. These molecules are ...
Background Cryptic Epitopes (CE) are peptides derived from the translation of one or more of the five alternative reading frames (ARFs; 2 sense and 3 antisense) of genes. Here, we compared response rates to HIV-1 specific CE predicted to be restricted by HLA-I alleles associated with protection against disease progression to those without any such association. Methods Peptides (9–11mer) were designed based on HLA-I binding algorithms for B*27, B*57 or B*5801 (protective alleles) and HLA-B*5301 or B*5501 (non-protective allele) in all five ARFs of the nine HIV-1 encoded proteins. Peptides with >50% probability of being an epitope (n=231) were tested for T cell responses in an IFN-γ ELISpot assay. PBMC samples from HIV-1 seronegative donors (n=42) and HIV-1 seropositive patients with chronic clade B infections (n=129) were used. Results Overall, 16%, 2%, and 2% of CHI patients had CE responses by IFN-γ ELISpot in the protective, non-protective, and seronegative groups, respectively (p=0.009, Fischer’s exact test). Twenty novel CE specific responses were mapped (median magnitude of 95 SFC/106 PBMC) and the majority were both anti-sense derived (90%) as well as represented ARFs of accessory proteins (55%). CE-specific CD8 T cells were multifunctional and proliferated when assessed by intracellular cytokine staining. Conclusions CE responses were preferentially restricted by the protective HLA-I alleles in HIV-1 infection suggesting that they may contribute to viral control in this group of patients.
Due to the increasing amount of people afflicted worldwide with Chagas disease and an increasing prevalence in the United States, there is a greater need to develop a safe and effective vaccine for this neglected disease. Adenovirus serotype 5 (Ad5) is the most common adenovirus vector used for gene therapy and vaccine approaches, but its efficacy is limited by preexisting vector immunity in humans resulting from natural infections. Therefore, we have employed rare serotype adenovirus 48 (Ad48) as an alternative choice for adenovirus/Chagas vaccine therapy. In this study, we modified Ad5 and Ad48 vectors to contain T. cruzi’s amastigote surface protein 2 (ASP-2) in the adenoviral early gene. We also modified Ad5 and Ad48 vectors to utilize the “Antigen Capsid-Incorporation” strategy by adding T. cruzi epitopes to protein IX (pIX). Mice that were immunized with the modified vectors were able to elicit T. cruzi-specific humoral and cellular responses. This study indicates that Ad48-modified vectors function comparable to or even premium to Ad5-modified vectors. This study provides novel data demonstrating that Ad48 can be used as a potential adenovirus vaccine vector against Chagas disease.
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.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.