Loss-of-function mutations within the IL-2 inducible kinase ITK in patients with EBV-associated lymphoproliferative diseases

Abstract

The purpose of this study was the appraisal of the clinical and functional consequences of germline mutations within the gene for the IL-2 inducible T-cell kinase, ITK. Among patients with Epstein-Barr virus-driven lymphoproliferative disorders (EBV-LPD), negative for mutations in SH2D1A and XIAP (n ¼ 46), we identified two patients with R29H or D500T,F501L,M503X mutations, respectively. Human wild-type (wt) ITK, but none of the mutants, was able to rescue defective calcium flux in murine Itk À/À T cells. Pulse-chase experiments showed that ITK mutations lead to varying reductions of protein half-life from 25 to 69% as compared with wt ITK (107 min). The pleckstrin homology domain of wt ITK binds most prominently to phosphatidylinositol monophosphates (PI(3)P, PI(4)P, PI(5)P) and to lesser extend to its double or triple phosphorylated derivates (PIP2, PIP3), interactions which were dramatically reduced in the patient with the ITK R29H mutant. ITK mutations are distributed over the entire protein and include missense, nonsense and indel mutations, reminiscent of the situation in its sister kinase in B cells, Bruton's tyrosine kinase.

Interleukin-2-Inducible T-Cell Kinase (ITK) Deficiency - Clinical and Molecular Aspects

“…In one patient a deletion led to a truncated SH2 and deleted kinase domain. Interestingly, in BTK , homologous mutations have been reported to cause X-linked agammaglobulinemia and the observed mutations in our eight patients have mutations in corresponding BTK residues indicating similar structural alterations [13]. …”

“…Calcium response was assayed by flux studies in transformed HVS patient T lymphocytes after CD3 antibody dependent TCR stimulation showing clearly reduced or nearly absent cytosolic release of calcium ions in most patients. TCR-mediated calcium mobilization was restored in murine Itk −/− thymocytes after transduction of a wild type ITK construct [13]. …”

Targets for Ibrutinib Beyond B Cell Malignancies

“…Moreover, CD44 high CD62L − CD4 + T cells are slightly increased in TEC KO mice, and they produce more IL‐17 upon activation when compared to WT mice 43. ITK mutations in humans have been reported in several cases of a fatal Epstein–Barr virus (EBV)‐associated lymphoproliferative disorder 44, 45. ITK KO mice show altered T cell development and mature T cell effector function, affecting in particular conventional T cells, thus leading to increased numbers of CD4 + T cells with a CD44 high CD62L − memory phenotype and CD8 + T cells, with a CD44 high CD62L + innate‐like phenotype, that upon stimulation rapidly secrete high levels of effector cytokines such as IFN‐ γ 46.…”

Deficiency of caspase recruitment domain family, member 11 (CARD11), causes profound combined immunodeficiency in human subjects

“…Other defects preferentially affect T-cell subpopulations, whereas total T-cell counts can be normal. [6][7][8] Therefore key signaling molecules downstream of the antigen receptors are prime candidates underlying profound combined immunodeficiency disorders (pCIDs). Caspase recruitment domain family, member 11 (CARD11), belongs to the family of membrane-associated guanylate kinases, which play a crucial role in the differentiation of both neuronal and immunologic tissues as scaffold proteins, facilitating the assembly of clusters of signaling molecules at sites of cell-cell contact.…”