NF-κB-inducing kinase (NIK), the essential upstream kinase, which regulates activation of the noncanonical NF-κB pathway, has important roles in regulating immunity and inflammation. In addition, NIK is vital for maintaining cellular health through its control of fundamental cellular processes, including differentiation, growth, and cell survival. As such aberrant expression or regulation of NIK is associated with several disease states. For example, loss of NIK leads to severe immune defects, while the overexpression of NIK is observed in inflammatory diseases, metabolic disorders, and the development and progression of cancer. This review discusses recent studies investigating the therapeutic potential of NIK inhibitors in various diseases.

Targeting NF-κB-Inducing Kinase (NIK) in Immunity, Inflammation, and Cancer.

The actin cytoskeleton is composed of dynamic filament networks that build adaptable local architectures to sustain nearly all cellular activities in response to a myriad of stimuli. Although the function of numerous players that tune actin remodeling is known, the coordinated molecular orchestration of the actin cytoskeleton to guide cellular decisions is still ill defined. T lymphocytes provide a prototypical example of how a complex program of actin cytoskeleton remodeling sustains the spatio-temporal control of key cellular activities, namely antigen scanning and sensing, as well as polarized delivery of effector molecules, via the immunological synapse. We here review the unique knowledge on actin dynamics at the T lymphocyte synapse gained through the study of primary immunodeficiences caused by mutations in genes encoding actin regulatory proteins. Beyond the specific roles of individual actin remodelers, we further develop the view that these operate in a coordinated manner and are an integral part of multiple signaling pathways in T lymphocytes.

/pdf/actin-dynamics-at-the-t-cell-synapse-as-revealed-by-immune-3rgaoa0cx3.pdf

Actin Dynamics at the T Cell Synapse as Revealed by Immune-Related Actinopathies.

Angioimmunoblastic T cell lymphoma (AITL) is a distinct subtype of peripheral T cell lymphoma and associated with poor outcomes. The activation status of T cell receptor (TCR) signaling has recently become a focus of attention in terms of the therapeutic targets. However, the molecular pathogenesis mechanisms and novel therapeutic targets are largely unknown. Antibodies specific to phosphorylated ZAP70, ITK and PLCγ1 were used to identify the activation status of intracellular proteins involved in TCR signaling in AITL patients. Malignant T cell lymphoma cells were transduced with a lentiviral construct containing ITK shRNA for cellular and functional assays. The antitumor effects of the selective ITK inhibitor BMS-509744 were determined in vitro and in vivo. Immunohistochemistry staining showed that more than half of the AITL patients (n = 38) exhibited continuously activated intracellular TCR signaling pathway. Patients positive for phosphorylated ITK showed a lower rate of complete response (20% vs. 75%, P = 0.004) and a shorter progression-free survival (5.17 months vs. 25.1 months, P = 0.022) than patients negative for phosphorylated ITK. Genetic and pharmacological cellular ITK inhibition significantly compromised the proliferation, invasion and migration of malignant T cells. The selective ITK inhibitor BMS-509744 also induced the pro-apoptotic effects and G2/M phase cell cycle arrest in vitro and in vivo. Finally, inhibition of ITK synergistically enhanced the antitumor effect of vincristine and doxorubicin on malignant T cell lymphoma cell lines. Our findings suggest that ITK may be a novel candidate therapeutic target for the treatment of patients with ITK-expressing malignant T-cell lymphomas.

/pdf/itk-inhibition-induced-in-vitro-and-in-vivo-anti-tumor-4nfm8whdsy.pdf

ITK inhibition induced in vitro and in vivo anti-tumor activity through downregulating TCR signaling pathway in malignant T cell lymphoma

Memory T cells play an essential role in protecting against infectious diseases and cancer and contribute to autoimmunity and transplant rejection. Understanding how they are generated and maintained in the context of infection or vaccination holds promise to improve current immune-based therapies. At the beginning of any immune response, naïve T cells are activated and differentiate into cells with effector function capabilities. In the context of infection, most of these cells die once the pathogenic antigen has been cleared. Only a few of them persist and differentiate into memory T cells. These memory T cells are essential to host immunity because they are long-lived and can perform effector functions immediately upon re-infection. How a cell becomes a memory T cell and continues being one for months and even years past the initial infection is still not fully understood. Recent reviews have thoroughly discussed the transcriptional, epigenomic, and metabolic mechanisms that govern T cell memory differentiation. Yet much less is known of how signaling pathways that are common circuitries of multiple environmental signals regulate T cell outcome and, precisely, T cell memory. The function of the NFκB signaling system is perhaps best understood in innate cells. Recent findings suggest that NFκB signaling plays an essential and unique role in generating and maintaining CD8 T cell memory. This review aims to summarize these findings and discuss the remaining questions in the field.

/pdf/nfkb-signaling-in-t-cell-memory-16aw42ue.pdf

NFκB signaling in T cell memory

The non-canonical nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway is an important component of NF-κB transcription complex. Activation of this pathway mediates the development and function of host immune system involved in inflammation and viral infection. During hepatitis B virus (HBV) infection, there is a complex interaction between infected hepatocytes and the immune cells, which can hinder antiviral immune responses and is associated with pathological changes in liver tissue. Consistently, the host immune system is closely related to the severity of liver damage and the level of viral replication. Previous studies indicated that the non-canonical NF-κB signaling pathway was affected by HBV and might play an important regulatory role in the antiviral immunity. Therefore, systematically elucidating the interplay between HBV and non canonical NF-κB signaling will contribute the discovery of more potential therapeutic targets and novel drugs to treat HBV infection.

/pdf/interplay-between-non-canonical-nf-kb-signaling-and-3535idmz9x.pdf

Interplay Between Non-Canonical NF-κB Signaling and Hepatitis B Virus Infection.

Multiple sclerosis (MS) is an inflammatory T cell-mediated disease of the central nervous system (CNS) (1). It is characterized by focal demyelination and axonal loss leading to a range of symptoms including decline in motor function and sense perception (2). In PNAS, Sabatino et al. (3) further shed light on the underlying mechanism of current MS therapies.

In mice, MS can be modeled by immunization with myelin-derived antigens, leading to a disease termed experimental autoimmune encephalomyelitis (EAE) (4). Many studies have defined the cells that are important in the activation of the T cells involved in EAE (5) as well as the role of the T cells involved in disease pathogenesis (6). In humans, neither a definite genetic nor environmental cause has been defined, nor has a cure been discovered for MS (7). Nevertheless, genetic studies have shown that genes of the immune system are highly associated with disease development (8). Importantly, one … 

[↵][1]1To whom correspondence may be addressed. Email: waisman{at}uni-mainz.de.

 [1]: #xref-corresp-1-1

Unraveling the T-B Tangle in anti-CD20 Multiple Sclerosis Therapy

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) characterized by neuronal and axonal damage resulting in a decline in motor and sensory functions (1). Although the ultimate cause of the disease has yet to be defined, the immune system and, in particular, pathogenic T cells play an unarguably important role in disease onset and progression (2). In PNAS, Morianos et al. extend our knowledge of how pathogenic T cells are regulated during neuroinflammation (3).

Many MS patients develop disease in the form of a relapsing-remitting MS (RRMS) in early age, of which a high percentage progress into the primary progressive form (PPMS). Only a minority of patients develop a PPMS form without having been in relapsing-remitting state before (4). Relapse and disease progression are associated with activated immune cells, such as plasma cells producing oligoclonal Ig bands detectable in the cerebrospinal fluid (CSF) or clonally expanding CD8+ T cells as well as cytotoxic CD4+ T cells in active lesions of MS patients (5⇓⇓–8). Interestingly, Morianos et al. (3) find increased levels of the cytokine activin-A in the CSF of RRMS patients in the remitting phase, suggesting a role of this cytokine in modulating the immune … 

[↵][1]1To whom correspondence may be addressed. Email: waisman{at}uni-mainz.de.

 [1]: #xref-corresp-1-1

Time to activin on pathogenic T cells.

NF-κB inducing kinase (NIK) is an essential post-transcriptional regulator of T-cell activation affecting F-actin dynamics and TCR signaling.

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Unraveling the T-B Tangle in anti-CD20 Multiple Sclerosis Therapy

Time to activin on pathogenic T cells.

NF-κB inducing kinase (NIK) is an essential post-transcriptional regulator of T-cell activation affecting F-actin dynamics and TCR signaling.