Targeting ITK signaling for T cell-mediated diseases

Abstract

The focus of this review is to examine the role of ITK signaling in multiple diseases and investigate the clinical potential of ITK inhibition. The diseases and potential interventions reviewed include T cell-derived malignancies as well as other neoplastic diseases, allergic diseases such as asthma and atopic dermatitis, certain infectious diseases, several autoimmune disorders such as rheumatoid arthritis and psoriasis, and finally the use of ITK inhibition in both solid organ and bone marrow transplantation recipients.

Keywords: Biochemistry; Biological sciences; Cell biology; Immunology; Molecular biology.

Graphical abstract

Figure 1

Targeting SLP76:ITK interaction a with a novel and specific inhibitors has a therapeutic potential To generate a molecule that specifically inhibits the interaction between pY145 of SLP76 and the SH2 domain of ITK, we designed a peptide based on the amino acid sequence of SLP76 from N132 to A155, which contains a phosphorylated tyrosine residue at Y145. The interaction between ITK and SLP76 involves the phospho-tyrosines at position pY145 and the proline-rich domain (PRD) of SLP76 docking onto the SH2 and SH3 domains of ITK, respectively. This multivalent anchoring of ITK on the different SLP76 docking sites results in distinct downstream signaling effects. This SLP76pTYR peptide significantly reduced IFN-γ and TNF-α production by TCR-stimulated T cells. Disrupting the SLP76:ITK interaction also significantly reduces PLC-γ1, ERK, P13K, and NF-κB phosphorylation. Inhibition of ITK enhances FOXP3⁺ regulatory T cells.

Figure 2

ITK is a critical for several T cells mediated diseases Selective inhibition of SLP76:ITK signaling will have a significant impact on T cell lymphoma, owing to Th1 cell expansion and increased T-bet and Eomes expression. This inhibition might also have an impact on allergic diseases, owing to Th2 cell reduction and decreased GATA3 expression. ITK inhibition will have an impact on autoimmune diseases owing to Th17 cell reduction and reduced expression of RORγt. The inhibition of ITK upregulates FOXP3-positive Tregs, which are critical for improving organ transplantation outcomes.

Figure 3

Targeting ITK can differentiate GVHD from CVL Current treatments to suppress GVHD following allo-HSCT often involve general immunosuppressive agents, such as cyclosporine A, which block donor T cell receptor (TCR)-mediated signaling and hence block general T cell activation. However, these agents can simultaneously inhibit GVL effects, increasing the chance of relapse. Thus, the identification of TCR-mediated signaling pathways that selectively maintain GVL effects while attenuating GVHD would be an optimal therapeutic intervention to differentiate GVHD from GVL. GVHD and GVL are mediated by the same donor T cells. Therefore, it is essential to understand which functions of T cells are critical for GVHD and which are important for GVL function. These donor T cell functions include donor T cell trafficking to GVHD target organs, inflammatory cytokine production by donor T cells, and cytotoxicity against tumor cells.