TEC and MAPK Kinase Signalling Pathways in T helper (TH) cell Development, TH2 Differentiation and Allergic Asthma

Abstract

Significant advances in our understanding of the signalling events during T cell development and differentiation have been made in the past few decades. It is clear that ligation of the T cell receptor (TCR) triggers a series of proximal signalling cascades regulated by an array of protein kinases. These orchestrated and highly regulated series of events, with differential requirements of particular kinases, highlight the disparities between αβ⁺CD4⁺ T cells. Throughout this review we summarise both new and old studies, highlighting the role of Tec and MAPK in T cell development and differentiation with particular focus on T helper 2 (T_H2) cells. Finally, as the allergy epidemic continues, we feature the role played by T_H2 cells in the development of allergy and provide a brief update on promising kinase inhibitors that have been tested in vitro, in pre-clinical disease models in vivo and into clinical studies.

Figure 1. Proximal TCR signaling

Following TCR engagement protein tyrosine kinases (PTKs) such as Lck, phosphorylate the tyrosine residues in the ITAMs in the cytoplasmic tails of CD3ζζ, which serve as docking sites for the Src homology 2 (SH2) domain containing tyrosine kinase ZAP-70. ZAP-70 phosphorylates adaptor proteins, including LAT and SLP-76, activating PI3-kinase pathway, Ras-MAPK pathways and Ca²⁺-mediated signalling. In the appropriate cytokine environment (red cytokines), CD4⁺ T cells differentiate into reversible T_H1, T_H2, T_H9, T_H17 and T_reg cells and secrete a suite of characteristic cytokines (blue, bold cytokines).

Figure 2. Tec kinases structure and their differential roles

The different members of the Tec kinase family are shown in a schematic. The proteins typically encode a N terminal pleckstrin homology domain (PH), followed by a Btk homology domain (BH), a proline rich region (PRR), a Src homology 3 (SH3) domain, a SH2 domain and a carboxy terminal kinase domain. Rlk, unlike the other members, encodes a palmitoylated string of cysteine residues on its amino terminal domain. Itk is expressed maximally in and is important for T_H2 differentiation, while Rlk has a significant role in regulating T_H1 cells. The role of Itk in T_H1 cells is unclear, while Rlk may compensate for Itk function in Itk^−/− cells. BMS-509744 is a pharmacological inhibitor of Itk.

Figure 3. MAPK activation cascade

MAPKs are activated in response to G-protein coupled receptors (GPCRs), growth factors, mitogens, pathogen associated molecular patterns (PAMPs) like LPS, inflammatory cytokines and environmental stresses. The kinase signalling cascade is organized into a three-tier system, with the activated MAP3Ks activating MAP2Ks, which in turn activate the MAPKs. There is significant crosstalk between the pathways and different MAPKs can activate different T_H cell specific transcription factors, that signal the T cells to differentiate accordingly. ERKs and p38 family members are specific for T_H2 and T_H1 cells respectively. While the role of p38 in T_H2 cells remains debated, JNKs are specific inhibitors of T_H2 cells. The different pharmacological inhibitors of the MAPKs are also shown.