The POSH/JIP‐1 scaffold network regulates TCR‐mediated JNK1 signals and effector function in CD8⁺T cells

Abstract

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 ...

POSH Regulates CD4+ T Cell Differentiation and Survival

“…The POSH scaffold complex regulates JNK1 dependent programs of effector function and proliferation in CD8 + T cells (17). JNK activity contributes to proliferation and survival of CD4 + T cells (32, 34, 37, 39, 40).…”

“…IP-FCM was performed using α-POSH (YY-5) or α-JIP-1 (2J8) CML beads as previously described (17, 38). In brief, >1,500 bead events were collected for each experiment and data was analyzed using FlowJo (TreeStar).…”

“…More recently, we have identified the molecule Plenty of SH3 domains (POSH) as a scaffold protein that facilitates JNK1 activation in CD8 + T cells (17). …”

“…POSH regulates several cell functions depending on which molecules bind to the different domains of POSH. For example, components of the JNK signaling pathway have been found in shared complexes with POSH (MAP3Ks, MKK7, JNK1 and JNK2) (17, 19–21). Functionally, POSH cooperates with JIP-1 to regulate JNK-dependent apoptosis in mature sympathetic neurons (19, 20).…”

“…Whether POSH also regulates these diverse functions in T cells is unclear. We were the first to identify a functional role of POSH in CD8 + T cells (17). However, the role of POSH in CD4 + T cells remains unknown.…”