T Cell Receptor-initiated Calcium Release is Uncoupled from Capacitative Calcium Entry in Itk-deficient T Cells

Overview

Journal J Exp Med

Specialties Allergy & Immunology
General Medicine

Date 1998 Jun 13

PMID 9584150

Citations 120

Authors

K Q Liu

S C Bunnell

C B Gurniak

L J Berg

Affiliations

Soon will be listed here.

Abstract

Itk, a Tec family tyrosine kinase, plays an important but as yet undefined role in T cell receptor (TCR) signaling. Here we show that T cells from Itk-deficient mice have a TCR-proximal signaling defect, resulting in defective interleukin 2 secretion. Upon TCR stimulation, Itk-/- T cells release normal amounts of calcium from intracellular stores, but fail to open plasma membrane calcium channels. Since thapsigargin-induced store depletion triggers normal calcium entry in Itk-/- T cells, an impaired biochemical link between store depletion and channel opening is unlikely to be responsible for this defect. Biochemical studies indicate that TCR-induced inositol 1,4,5 tris-phosphate (IP3) generation and phospholipase C gamma1 tyrosine phosphorylation are substantially reduced in Itk-/- T cells. In contrast, TCR-zeta and ZAP-70 are phosphorylated normally, suggesting that Itk functions downstream of, or in parallel to, ZAP-70 to facilitate TCR-induced IP3 production. These findings support a model in which quantitative differences in cytosolic IP3 trigger distinct responses, and in which only high concentrations of IP3 trigger the influx of extracellular calcium.

Citing Articles

Purification and characterization of full-length monomeric TEC family kinase, ITK.

Rathnayake U, Wada J, Wall V, Jones J, Jenkins L, Andreotti A Protein Expr Purif. 2025; 229:106682.

PMID: 39894064 PMC: 11875054. DOI: 10.1016/j.pep.2025.106682.

Genetics of Primary Hemophagocytic Lymphohistiocytosis.

Karageorgos S, Platt A, Bassiri H Adv Exp Med Biol. 2024; 1448:75-101.

PMID: 39117809 DOI: 10.1007/978-3-031-59815-9_7.

When to suspect inborn errors of immunity in Epstein-Barr virus-related lymphoproliferative disorders.

Sacco K, Notarangelo L, Delmonte O Clin Microbiol Infect. 2022; 29(4):457-462.

PMID: 36209991 PMC: 10066820. DOI: 10.1016/j.cmi.2022.10.003.

Recognition of Immune Cell Markers of COVID-19 Severity with Machine Learning Methods.

Chen L, Mei Z, Guo W, Ding S, Huang T, Cai Y Biomed Res Int. 2022; 2022:6089242.

PMID: 35528178 PMC: 9073549. DOI: 10.1155/2022/6089242.

T cell receptor (TCR) signaling in health and disease.

Shah K, Al-Haidari A, Sun J, Kazi J Signal Transduct Target Ther. 2021; 6(1):412.

PMID: 34897277 PMC: 8666445. DOI: 10.1038/s41392-021-00823-w.

References

Weiss A, Wiskocil R, Stobo J . The role of T3 surface molecules in the activation of human T cells: a two-stimulus requirement for IL 2 production reflects events occurring at a pre-translational level. J Immunol. 1984; 133(1):123-8. View

Heyeck S, Wilcox H, Bunnell S, Berg L . Lck phosphorylates the activation loop tyrosine of the Itk kinase domain and activates Itk kinase activity. J Biol Chem. 1997; 272(40):25401-8. DOI: 10.1074/jbc.272.40.25401. View

Thastrup O, Cullen P, Drobak B, Hanley M, Dawson A . Thapsigargin, a tumor promoter, discharges intracellular Ca2+ stores by specific inhibition of the endoplasmic reticulum Ca2(+)-ATPase. Proc Natl Acad Sci U S A. 1990; 87(7):2466-70. PMC: 53710. DOI: 10.1073/pnas.87.7.2466. View

Gouy H, Cefai D, Christensen S, Debre P, Bismuth G . Ca2+ influx in human T lymphocytes is induced independently of inositol phosphate production by mobilization of intracellular Ca2+ stores. A study with the Ca2+ endoplasmic reticulum-ATPase inhibitor thapsigargin. Eur J Immunol. 1990; 20(10):2269-75. DOI: 10.1002/eji.1830201016. View

Weiss A, Koretzky G, Schatzman R, Kadlecek T . Functional activation of the T-cell antigen receptor induces tyrosine phosphorylation of phospholipase C-gamma 1. Proc Natl Acad Sci U S A. 1991; 88(13):5484-8. PMC: 51901. DOI: 10.1073/pnas.88.13.5484. View

Harding F, McArthur J, Gross J, Raulet D, Allison J . CD28-mediated signalling co-stimulates murine T cells and prevents induction of anergy in T-cell clones. Nature. 1992; 356(6370):607-9. DOI: 10.1038/356607a0. View

Heyeck S, Berg L . Developmental regulation of a murine T-cell-specific tyrosine kinase gene, Tsk. Proc Natl Acad Sci U S A. 1993; 90(2):669-73. PMC: 45725. DOI: 10.1073/pnas.90.2.669. View

Vetrie D, Vorechovsky I, Sideras P, Holland J, Davies A, Flinter F . The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases. Nature. 1993; 361(6409):226-33. DOI: 10.1038/361226a0. View

Tsukada S, Saffran D, Rawlings D, Parolini O, Allen R, Klisak I . Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia. Cell. 1993; 72(2):279-90. DOI: 10.1016/0092-8674(93)90667-f. View

10.

Berridge M . Inositol trisphosphate and calcium signalling. Nature. 1993; 361(6410):315-25. DOI: 10.1038/361315a0. View

11.

Wacholtz M, Lipsky P . Anti-CD3-stimulated Ca2+ signal in individual human peripheral T cells. Activation correlates with a sustained increase in intracellular Ca2+1. J Immunol. 1993; 150(12):5338-49. View

12.

Thomas J, Sideras P, Smith C, Vorechovsky I, Chapman V, Paul W . Colocalization of X-linked agammaglobulinemia and X-linked immunodeficiency genes. Science. 1993; 261(5119):355-8. DOI: 10.1126/science.8332900. View

13.

Rawlings D, Saffran D, Tsukada S, Largaespada D, Grimaldi J, Cohen L . Mutation of unique region of Bruton's tyrosine kinase in immunodeficient XID mice. Science. 1993; 261(5119):358-61. DOI: 10.1126/science.8332901. View

14.

Putney Jr J, Bird G . The signal for capacitative calcium entry. Cell. 1993; 75(2):199-201. DOI: 10.1016/0092-8674(93)80061-i. View

15.

Elder M, Lin D, Clever J, Chan A, Hope T, Weiss A . Human severe combined immunodeficiency due to a defect in ZAP-70, a T cell tyrosine kinase. Science. 1994; 264(5165):1596-9. DOI: 10.1126/science.8202712. View

16.

Chan A, Kadlecek T, Elder M, Filipovich A, Kuo W, Iwashima M . ZAP-70 deficiency in an autosomal recessive form of severe combined immunodeficiency. Science. 1994; 264(5165):1599-601. DOI: 10.1126/science.8202713. View

17.

Conley M, Parolini O, Rohrer J, Campana D . X-linked agammaglobulinemia: new approaches to old questions based on the identification of the defective gene. Immunol Rev. 1994; 138:5-21. DOI: 10.1111/j.1600-065x.1994.tb00844.x. View

18.

Aoki Y, Isselbacher K, Pillai S . Bruton tyrosine kinase is tyrosine phosphorylated and activated in pre-B lymphocytes and receptor-ligated B cells. Proc Natl Acad Sci U S A. 1994; 91(22):10606-9. PMC: 45070. DOI: 10.1073/pnas.91.22.10606. View

19.

Liao X, Littman D . Altered T cell receptor signaling and disrupted T cell development in mice lacking Itk. Immunity. 1995; 3(6):757-69. DOI: 10.1016/1074-7613(95)90065-9. View

20.

Gibson S, August A, Kawakami Y, Kawakami T, DuPont B, Mills G . The EMT/ITK/TSK (EMT) tyrosine kinase is activated during TCR signaling: LCK is required for optimal activation of EMT. J Immunol. 1996; 156(8):2716-22. View