Alternative titles; symbols
HGNC Approved Gene Symbol: ITK
SNOMEDCT: 1186714005;
Cytogenetic location: 5q33.3 Genomic coordinates (GRCh38): 5:157,180,840-157,255,185 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q33.3 | Lymphoproliferative syndrome 1 | 613011 | Autosomal recessive | 3 |
The ITK gene encodes IL2 (147680)-inducible T-cell kinase, which is important for proper T-cell development, T-cell receptor (TCR) signaling, cytokine release, and regulation of differentiation. ITK is analogous to Bruton tyrosine kinase (BTK; 300300), which is specifically expressed in B cells and instrumental for their undisturbed development, differentiation, and signaling (summary by Linka et al., 2012).
Signal transduction through the T-cell receptor (TCR; see 186880) and cytokine receptors on the surface of T lymphocytes occurs largely via tyrosine phosphorylation of intracellular substrates. Signal transduction is thought to occur via association of these receptors with intracellular protein tyrosine kinases. To identify unique T-cell tyrosine kinases, Gibson et al. (1993) used PCR-based cloning with degenerate oligonucleotides directed at highly conserved motifs of tyrosine kinase domains. In this way, they cloned the complete cDNA for a unique human tyrosine kinase that is expressed mainly in T lymphocytes and natural killer (NK) cells. The cDNA predicted an open reading frame of 1,866 bp encoding a protein with a predicted size of 72 kD, which was in keeping with its size on Western blotting. A single 6.2-kb mRNA and 72-kD protein were detected in T lymphocytes and NK-like cell lines, but were not detected in other cell lineages. Sequence comparisons suggested that the protein is probably the human homolog of a murine interleukin-2-inducible T-cell kinase (ITK). However, unlike ITK, the message and protein levels for the new entity did not vary markedly on stimulation of human IL-2 responsive T cells with IL-2. They referred to the gene and its protein product as EMT ('expressed mainly in T cells'). They concluded that EMT is a member of a new family of intracellular kinases that includes BPK (the kinase mutant in X-linked agammaglobulinemia, 300300). The expression of EMT message and protein in thymocytes and mature T cells, combined with its homology to BPK and its chromosomal localization, suggested that EMT may play a role in thymic ontogeny and growth regulation of mature T cells.
ITK is the T-cell-specific homolog of Bruton tyrosine kinase (BTK), which is mutant in X-linked agammaglobulinemia (300300). Cheng et al. (1994) showed that BTK interacts with 3 protein-tyrosine kinases that get activated upon stimulation of B- and T-cell receptors. These interactions are mediated by two 10-amino acid motifs in BTK; an analogous site with the same specificity is also present in ITK.
Integrin adhesion receptors mediate critical interactions of T cells with other cells and extracellular matrix components during trafficking, as well as during antigen-specific recognition events in tissue. Phosphatidylinositol 3-kinase (PI3K; see 601232) has a role in the regulation of integrin activity by CD3 (see 186790)-TCR and in the regulation of ITK. Woods et al. (2001) determined that TCR-mediated activation of beta-1 integrins (see ITGB1; 135630) requires activation of ITK and PI3K-dependent recruitment of ITK to detergent-insoluble glycosphingolipid-enriched microdomains (DIGs) via binding of the pleckstrin homology domain of ITK to the PI3K product PI(3,4,5)-P3. Likewise, activation of PI3K and LCK (153390) via CD4 (186940) coreceptor stimulation can initiate beta-1 integrin activation dependent on ITK function. CD4 stimulation, together with targeting of ITK to DIGs, also activates TCR-independent beta-1 integrin function. Changes in beta-1 integrin function mediated by TCR-induced activation of ITK are accompanied by ITK-dependent modulation of the actin cytoskeleton. Woods et al. (2001) concluded that TCR-mediated activation of beta-1 integrin involves membrane relocalization and activation of ITK via coordinate action of PI3K and an SRC family tyrosine kinase.
Hwang et al. (2005) reported that TBET (604895) represses Th2 lineage commitment through tyrosine kinase-mediated interaction between itself and GATA3 (131320) that interferes with the binding of GATA3 to its target DNA. Hwang et al. (2005) concluded that their results provide a novel function for tyrosine phosphorylation of a transcription factor in specifying alternate fates of a common progenitor cell. Hwang et al. (2005) showed that TBET phosphorylation is restricted to the TEC kinases ITK and RLK (600058). Coexpression studies demonstrated that this was most efficiently performed by ITK. In primary CD4 T cells isolated from ITK-, RLK-, or double ITK/RLK-deficient mice, the greatest diminution of TBET tyrosine phosphorylation was seen in the absence of ITK. Furthermore, mutation of TBET at tyrosine residue 525, but not control tyrosine residue 437, resulted in greatly reduced phosphorylation by ITK, revealing that ITK phosphorylates TBET at residue Y525 after T cell receptor stimulation.
Huang et al. (2007) showed that phosphorylation of inositol 1,4,5-trisphosphate (IP3) into IP4 promoted pleckstrin homology domain binding to phosphatidylinositol 3,4,5-trisphosphate and was required for full activation of Itk in primary mouse thymocytes. They proposed that IP4 establishes a feedback loop of phospholipase C-gamma-1 (PLCG1; 172420) activation through ITK that is essential for T-cell development.
Gibson et al. (1993) mapped the EMT gene to chromosome 5q31-q32 by fluorescence in situ hybridization. By fluorescence in situ hybridization, Janis et al. (1994) mapped the human ITK gene to 5q32-q33. By Southern blot analysis of DNA from the progeny of 2 multilocus crosses, the murine Itk gene was mapped to chromosome 11 in a region of homology to human 5q. The region in humans is frequently deleted in the myelodysplastic syndrome.
In 2 sisters with autosomal recessive fatal EBV-associated lymphoproliferative syndrome-1 (LPFS1; 613011), Huck et al. (2009) identified a homozygous mutation in the ITK gene (R355W; 186973).
In 3 members of a consanguineous Arab family with lymphoproliferative syndrome-1, Stepensky et al. (2011) identified a homozygous truncating mutation in the ITK gene (Y588X; 186973.0002). The mutation, which was found by homozygosity mapping followed by candidate gene sequencing, segregated with the disorder in the family.
In a patient, born of consanguineous Moroccan parents, with lymphoproliferative syndrome-1, Linka et al. (2012) identified a homozygous missense mutation in the ITK gene (R29H; 186973.0003). Linka et al. (2012) performed functional studies on cells from the patients reported by Huck et al. (2009), Stepensky et al. (2011), and Linka et al. (2012), and found that all had a reduced calcium signaling response after TCR stimulation and were unable to enhance calcium response in Itk-null mouse cells, consistent with a loss of function. In vitro studies showed that all mutant proteins had reduced half-lives; the R29H mutation impeded membrane targeting of ITK.
By homologous recombination, Schaeffer et al. (1999) disrupted the Rlk (TXK; 600058) gene in mice. Heterozygotes were completely normal. Homozygous null Rlk mice showed increased amounts of Itk mRNA. The authors hypothesized that upregulation of related Tec kinases may partially compensate for the lack of Rlk. Schaeffer et al. (1999) therefore generated Rlk -/- Itk -/- mice by interbreeding. Itk-deficient mice have reduced numbers of mature T cells, particularly CD4+ cells, causing a decreased CD4-to-CD8 ratio. Rlk -/- Itk -/- mutants, however, had normal T cell numbers. Both CD4+ and CD8+ cell numbers are increased relative to Itk -/- mice. The persistent abnormal ratio of CD4+ to CD8+ cells suggested an altered regulation of lymphoid development and homeostasis in the double mutants. The double mutants had marked defects in T-cell receptor responses including proliferation, cytokine production, and apoptosis in vitro and adaptive immune responses to Toxoplasma gondii in vivo. Molecular events immediately downstream from the T-cell receptor were intact in Rlk -/- Itk -/- cells, but intermediate events including inositol trisphosphate production, calcium mobilization, and mitogen-activated protein kinase activation were impaired, establishing Tec kinases as critical regulators of T-cell receptor signaling required for phospholipase C-gamma activation.
Using flow cytometry, Dubois et al. (2006) found that Il15 (600554) -/- mice lacked Cd44 (107269)-hi/Cd122 (IL2RB; 146710)-hi memory phenotype Cd8-positive T cells in both the periphery and thymus, whereas Itk -/- mice lacked Cd44-lo/Cd122-lo naive Cd8-positive T cells in the periphery and thymus. Mice lacking both Itk and Il15 had a severe reduction of all CD8-positive T cells. Dubois et al. (2006) proposed that there are 2 distinct populations of CD8-positive T cells dependent on ITK or IL15, and that the IL15-dependent CD44-hi/CD122-hi memory phenotype CD8-positive T cells have functions in both innate and adaptive immunity.
Broussard et al. (2006) found that Cd8-positive T cells from mice lacking Itk or both Itk and Rlk expressed memory markers (e.g., Cd44 and Cd122) and rapidly produced Ifng (147570). Itk deficiency greatly increased the number of cells selected by MHC class Ib. Broussard et al. (2006) concluded that the absence of TEC kinases prevents conventional CD8-positive T-cell development and leads to generation of a large population of nonconventional innate-type CD8-positive T cells. Atherly et al. (2006) presented similar findings.
In 2 Turkish sisters, born of consanguineous parents, with fatal EBV-associated lymphoproliferative syndrome-1 (LPFS1; 613011), Huck et al. (2009) identified a homozygous 1085C-T transition in exon 11 of the ITK gene, resulting in an arg335-to-trp (R335W) substitution in a highly conserved residue in the BG loop of the SH2 domain. Attempts to functionally express the R335W mutant in bacteria failed due to aggregation of the recombinant protein, whereas wildtype protein was stable and expressed functionally at high levels. Functional expression in 293T cells showed mRNA expression of the mutant transcript, but nearly undetectable ITK protein, consistent with severe protein instability. Both girls developed chronic active EBV infection in early childhood that was resistant to treatment. The disorder progressed to lymphadenopathy, hepatosplenomegaly, B-cell proliferation, and Hodgkin lymphoma in 1 girl. There were extremely low levels of the protein in lymph node biopsy from 1 of the girls. Both unaffected parents were heterozygous for the mutation. The mutation was not identified in 100 Turkish and 100 German children.
Linka et al. (2012) showed that cells from the patients reported by Huck et al. (2009) had a reduced calcium signaling response after TCR stimulation and were unable to enhance calcium response in Itk-null mouse cells, consistent with a loss of function.
In 3 members of a consanguineous Arab family with lymphoproliferative syndrome-1 (LPFS1; 613011), Stepensky et al. (2011) identified a homozygous c.1764C-G transversion in exon 16 of the ITK gene, resulting in a tyr588-to-ter (Y588X) substitution that would disrupt the ITK kinase domain. The mutation, which was found by homozygosity mapping followed by candidate gene sequencing, segregated with the disorder in the family. The patients presented between ages 3 and 5 years with fever, lymphadenopathy, and Hodgkin lymphoma associated with EBV infection. One patient was treated successfully with chemotherapy but later developed fatal hemophagocytic lymphohistiocytosis; the second patient was treated successfully with chemotherapy but later developed autoimmune renal disease and was treated successfully with antiviral therapy; and the third patient underwent successful bone marrow transplant from a donor sib who was heterozygous for the mutation.
Linka et al. (2012) showed that cells from the patient reported by Stepensky et al. (2011) had a reduced calcium signaling response after TCR stimulation and were unable to enhance calcium response in Itk-null mouse cells, consistent with a loss of function.
In a patient, born of consanguineous Moroccan parents, with lymphoproliferative syndrome-1 (LPFS1; 613011), Linka et al. (2012) identified a homozygous c.86G-A transition in the ITK gene, resulting in an arg29-to-his (R29H) substitution in the pleckstrin homology domain. The patient was diagnosed at age 11 years with an EBV-associated B-cell lymphoproliferative disorder. He also had autoimmune hemolytic anemia, thrombocytopenia, and progressive lymphopenia. He died at age 26 years. Patient cells had a reduced calcium signaling response after TCR stimulation and were unable to enhance calcium response in Itk-null mouse cells, consistent with a loss of function. In vitro studies showed that the R29H mutation impeded membrane targeting of ITK.
Atherly, L. O., Lucas, J. A., Felices, M., Yin, C. C., Reiner, S. L., Berg, L. J. The Tec family kinases Itk and Rlk regulate the development of conventional CD8+ T cells. Immunity 25: 79-91, 2006. [PubMed: 16860759] [Full Text: https://doi.org/10.1016/j.immuni.2006.05.012]
Broussard, C., Fleischacker, C., Horai, R., Chetana, M., Venegas, A. M., Sharp, L. L., Hedrick, S. M., Fowlkes, B. J., Schwartzberg, P. L. Altered development of CD8+ T cell lineages in mice deficient for the Tec kinases Itk and Rlk. Immunity 25: 93-104, 2006. Note: Erratum: Immunity 25: 849 only, 2006. [PubMed: 16860760] [Full Text: https://doi.org/10.1016/j.immuni.2006.05.011]
Cheng, G., Ye, Z.-S., Baltimore, D. Binding of Bruton's tyrosine kinase to Fyn, Lyn, or Hck through a Src homology 3 domain-mediated interaction. Proc. Nat. Acad. Sci. 91: 8152-8155, 1994. [PubMed: 8058772] [Full Text: https://doi.org/10.1073/pnas.91.17.8152]
Dubois, S., Waldmann, T. A., Muller, J. R. ITK and IL-15 support two distinct subsets of CD8+ T cells. Proc. Nat. Acad. Sci. 103: 12075-12080, 2006. [PubMed: 16880398] [Full Text: https://doi.org/10.1073/pnas.0605212103]
Gibson, S., Leung, B., Squire, J. A., Hill, M., Arima, N., Goss, P., Hogg, D., Mills, G. B. Identification, cloning, and characterization of a novel human T-cell-specific tyrosine kinase located at the hematopoietin complex on chromosome 5q. Blood 82: 1561-1572, 1993. [PubMed: 8364206]
Huang, Y. H., Grasis, J. A., Miller, A. T., Xu, R., Soonthornvacharin, S., Andreotti, A. H., Tsoukas, C. D., Cooke, M. P., Sauer, K. Positive regulation of Itk PH domain function by soluble IP4. Science 316: 886-889, 2007. [PubMed: 17412921] [Full Text: https://doi.org/10.1126/science.1138684]
Huck, K., Feyen, O, Niehues, T., Ruschendorf, F., Hubner, N., Laws, H.-J., Telieps, T., Knapp, S., Wacker, H.-H., Meindl, A., Jumaa, H., Borkhardt, A. Girls homozygous for an IL-2-inducible T cell kinase mutation that leads to protein deficiency develop fatal EBV-associated lymphoproliferation. J. Clin. Invest. 119: 1350-1358, 2009. [PubMed: 19425169] [Full Text: https://doi.org/10.1172/jci37901]
Hwang, E. S., Szabo, S. J., Schwartzberg, P. L., Glimcher, L. H. T helper cell fate specified by kinase-mediated interaction of T-bet with GATA-3. Science 307: 430-433, 2005. [PubMed: 15662016] [Full Text: https://doi.org/10.1126/science.1103336]
Janis, E. M., Siliciano, J. D., Isaac, D. D., Griffin, C. A., Hawkins, A. L., Kozak, C. A., Desiderio, S. Mapping of the gene for the tyrosine kinase Itk to a region of conserved synteny between mouse chromosome 11 and human chromosome 5q. Genomics 23: 269-271, 1994. [PubMed: 7829087] [Full Text: https://doi.org/10.1006/geno.1994.1492]
Linka, R. M., Risse, S. L., Bienemann, K., Werner, M., Linka, Y., Krux, F., Synaeve, C., Deenen, R., Ginzel, S., Dvorsky, R., Gombert, M., Halenius, A., and 13 others. Loss-of-function mutations within the IL-2 inducible kinase ITK in patients with EBV-associated lymphoproliferative diseases. Leukemia 26: 963-971, 2012. [PubMed: 22289921] [Full Text: https://doi.org/10.1038/leu.2011.371]
Schaeffer, E. M., Debnath, J., Yap, G., McVicar, D., Liao, X. C., Littman, D. R., Sher, A., Varmus, H. E., Lenardo, M. J., Schwartzberg, P. L. Requirement for Tec kinases Rlk and Itk in T cell receptor signaling and immunity. Science 284: 638-641, 1999. [PubMed: 10213685] [Full Text: https://doi.org/10.1126/science.284.5414.638]
Stepensky, P., Weintraub, M., Yanir, A., Revel-Vilk, S., Krux, F., Huck, K., Linka, R. M., Shaag, A., Elpeleg, O., Borkhardt, A., Resnick, I. B. IL-2-inducible T-cell kinase deficiency: clinical presentation and therapeutic approach. Haematologica 96: 472-476, 2011. [PubMed: 21109689] [Full Text: https://doi.org/10.3324/haematol.2010.033910]
Woods, M. L., Kivens, W. J., Adelsman, M. A., Qiu, Y., August, A., Shimizu, Y. A novel function for the Tec family tyrosine kinase Itk in activation of beta-1 integrins by the T-cell receptor. EMBO J. 20: 1232-1244, 2001. [PubMed: 11250890] [Full Text: https://doi.org/10.1093/emboj/20.6.1232]