Inhibition, Nuclear factor kappa B (NF-kB) leads to Suppression of T cell activation

NF-kB plays a crucial role in the activation of dendritic cells as well as T cells. In dendritic cells,  the activation of the canonical NF-kB pathway in response to pro-inflammatory stimuli, such as cytokines including IL-1a or IL-1b and TLR ligands, stimulate the maturation of dendritic cells with enhanced antigen presenting function.  The inhibition of NF-kB suppress antigen presenting function of dendritic cells, resulting in suppression of T cell activation (reviewed by Reinhard et al (Reinhard et al., 2012) and van Delft et al (van Delft, Huitema and Tas, 2015).

In T cells, NF-kB can be activated by several pathways of signal transduction. The engagement of the TCR by major histocompatibility complex (MHC) plus antigen initiates downstream CD3 immunotyrosine activation motif (ITAM) phosphorylation by the Src family kinases, FYN and leukocyte C-terminal src kinase (LCK). Phosphorylated CD3 activates the T cell specific tyrosine kinase, zeta-chain associated protein kinase (ZAP-70), which ultimately trigger calcium release and protein kinase (PK)C activation, respectively. Activation of a specific PKC isoform, PKCμ, connects the above described TCR proximal signaling events to distal events that ultimately lead to NF-kB activation. Importantly, PKCm activation is also driven by engagement of the T cell co-stimulatory receptor CD28 by B7 ligands on antigen presenting cells (APCs). In addition, the stimulation of T cells by IL-1 activates NF-kB as already described before. Once in the nucleus, NF-kB governs the transcription of numerous genes involved in T cell survival, proliferation, and effector functions (Paul and Schaefer, 2013).

A representative NF-kB inhibitor, MG132 that suppresses NF-kB activity at more than 10 mM (Fiedler et al. 1998) suppresses IL-2-induced activation of STAT5 at 50 mM. (Yu and Malek., 2001). However, MG-132 did not decrease the effect of TNF-α on AP-1 activation (Fiedler, Wernke-Dollries and Stark, 1998).

A representative NF-kB inhibitor, DHMEQ (1μg/mL) blocked phytohaemagglutinin (PHA-)-induced nuclear translocation of NF-kB in Jurkat cells via inhibition of degradation of IkBa. Preincubation of peripheral blood mononuclear cells and Jurkat cells with DHMEQ (1 μg/ml, 3 hr) greatly reduced PHA-stimulated expression of IFN-, IL-2 and TNF- genes although DHMEQ alone without PHA-stimulation did not affect cytokine production in unstimulated PBMC. DHMEQ (0·5–3 μg/mL, 3 days) inhibited PHA-stimulated proliferation of peripheral blood mononuclear cells (PBMC) in a dose-dependent manner although did not affect the viability of resting PBMC under identical culture conditions. DHMEQ (3 μg/mL, 24 hr) induced apoptosis of PHA-stimulated PBMC. DHMEQ (0·5 μg/mL) decreased levels of TNF-α-stimulated expression of CD40 in monocyte-derived dendritic cells (DCs). Exposure of DCs to DHMEQ (0·5 or 1 μg/ml) reduced their endocytic ability (Nishioka et al., 2008).