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  • Review Article
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TEC-family kinases: regulators of T-helper-cell differentiation

Nature Reviews Immunology volume 5, pages 284–295 (2005)Cite this article

Key Points

  • The phenotypes of mice that are deficient in TEC-family kinases have previously been associated with defects in phospholipase C-γ1 activation and Ca2+ mobilization. Now, several studies indicate that the TEC-family kinase ITK (interleukin-2-inducible T-cell kinase) is also required for the actin reorganization and cell polarization that occurs after T-cell-receptor engagement.

  • There are striking similarities between T cells that are deficient in ITK and VAV1 with respect to biochemical and cellular defects, including impaired reorganization of actin, and effects on recruitment of protein kinase C-θ (PKC-θ) and activation of transcription factors.

  • Evidence implicates TEC-family kinases in the development of T helper (TH) cells.

  • Overexpression of RLK (resting lymphocyte kinase) by Jurkat T cells or in mice leads to skewed differentiation towards the TH1-cell lineage.

  • T cells from Itk−/− mice produce decreased levels of TH2 cytokines and fail to mount responses to several TH2-cell-inducing pathogens.

  • Mice that are deficient in VAV1 or PKC-θ also show TH2-cell defects, implying that there are common pathways regulating TH2-cell development.

  • The recent finding that specific inhibitors of ITK ameliorate disease in a mouse model of allergic asthma indicates that ITK is a potential therapeutic target for TH2-cell-mediated diseases.

  • The defective TH2-cell response to infection with Schistosoma mansoni that is observed in Itk−/− mice is rescued by deletion of RLK, despite the presence of more severe biochemical defects in Rlk−/−Itk−/− T cells. This indicates that global inhibitors of TEC-family kinases might not be ideal therapeutic agents.

  • A role for TEC in TH-cell development has not yet been examined, but recent findings indicate that this TEC-family kinase might have unique functions in effector T cells.

Abstract

The TEC-family protein tyrosine kinases ITK, RLK and TEC have been identified as key components of T-cell-receptor signalling that contribute to the regulation of phospholipase C-γ, the mobilization of Ca2+ and the activation of mitogen-activated protein kinases. Recent data also show that TEC kinases contribute to T-cell-receptor-driven actin reorganization and cell polarization, which are required for productive T-cell activation. Functional studies have implicated TEC kinases as important mediators of pathways that control the differentiation of CD4+ T helper cells. Here, we review studies of signalling pathways that involve TEC kinases and how these pathways might contribute to the regulation of T-helper-cell differentiation and function.

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Figure 1: Structure and activation of TEC-family kinases.
Figure 2: TEC-family kinases in T-cell-receptor-signalling pathways.
Figure 3: T-cell receptors and chemokine receptors signal through TEC-family kinases.
Figure 4: RLK and ITK in T-helper-cell development.

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Acknowledgements

The authors thank R. Houghtling and members of the Schwartzberg laboratory for helpful discussions, and A. Altman for permission to cite unpublished results.

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Authors and Affiliations

  1. National Human Genome Research Institute, National Institutes of Health, 4A38/49 Convent Drive, Bethesda, 20892, Maryland, USA

    Pamela L. Schwartzberg, Lisa D. Finkelstein & Julie A. Readinger

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  1. Pamela L. Schwartzberg
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  2. Lisa D. Finkelstein
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  3. Julie A. Readinger
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Correspondence to Pamela L. Schwartzberg.

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DATABASES

Entrez Gene

BMX

BTK

GATA3

ITK

MAF

NFATc1

PKC-θ

RLK

T-bet

TEC

VAV1

Glossary

X-LINKED AGAMMAGLOBULINAEMIA

(XLA). A human immunodeficiency that is caused by mutations in the gene encoding Bruton's tyrosine kinase (BTK), which is located on the X chromosome.These mutations result in a block in B-cell maturation and in poor antibody production. A naturally occurring mouse mutant of BTK, X-linked immunodeficiency (XID), is associated with less severe disease.

NON-RECEPTOR PROTEIN TYROSINE KINASES

Proteins that lack a transmembrane or extracellular domain, have no ligand, are found intracellularly and add a phosphate group to tyrosine residues in proteins. Tyrosine phosphorylation leads to a change in the ability of the phosphorylated protein to bind and activate downstream molecules.

T-HELPER-2-CELL RESPONSES

(TH2-cell responses). There are two main effector subsets of CD4+ T cells, which are characterized by distinct cytokine profiles and by functional activity. TH2 cells produce interleukin-4 (IL-4), IL-5, IL-9, IL-10 and IL-13, leading to activation of humoral immune responses. By contrast, TH1 cells produce interferon-γ, IL-2 and lymphotoxin, which support cell-mediated immunity. Appropriate differentiation of T cells into these subsets is important for mounting immune responses to different pathogens, whereas an imbalance between these subsets is associated with diseases, including asthma, hypersensitivity and autoimmune disorders.

ATOPIC DERMATITIS

A disease that is characterized by a scaly, itchy rash that is caused by inflammation of the skin and by increased production of T-helper-2 cytokines.

PHOSPHATIDYLINOSITOL-3,4,5-TRISPHOSPHATE

(PtdIns(3,4,5)P3). A product of phosphatidylinositol 3-kinase, which adds a phosphate group to phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2) to yield PtdIns(3,4,5)P3. PtdIns(3,4,5)P3 binds pleckstrin-homology-domain-containing proteins, resulting in membrane recruitment of these proteins and initiation of signalling cascades.

PLECKSTRIN-HOMOLOGY DOMAIN

A protein–lipid interaction domain that usually consists of 100 amino-acid residues. Pleckstrin-homology domains have little overall sequence homology but have conserved motifs and tertiary structure. They are thought to be involved in anchoring of proteins to the membrane and have been found to bind the following: phospholipids (including phosphatidylinositol-4,5-bisphosphate and phosphatidylinositol-3,4,5-trisphosphate), proteins (including the β and γ subunits of heterotrimeric G proteins), phosphorylated serine or threonine residues, and membranes.

SH3

(SRC homology 3). A protein-interaction domain that is commonly found in signal-transduction molecules. It specifically interacts with certain proline-containing peptides (containing either (R/K)XXPXXP or PXXPXR motifs, where X denotes any amino acid) to facilitate protein– protein interactions that are required for protein function or subcellular localization.

SH2

(SRC homology 2). A protein-interaction domain that is commonly found in signal-transduction molecules. It specifically interacts with phosphotyrosine-containing peptides.

PEPTIDYLPROLYL ISOMERASE

An enzyme that converts the peptide bond that is amino terminal to proline residues between cis and trans conformations. Cyclophilin A is a peptidylprolyl isomerase that acts on a proline residue present in ITK (interleukin-2-inducible T-cell kinase).

CYCLOPHILIN A

A well-known binding partner of the immunosuppressant cyclosporin. The cyclosporin– cyclophilin complex inhibits activation of calcineurin, a phosphatase that activates the NFAT (nuclear factor of activated T cells) family of transcription factors. Cyclophilin A is also a peptidylprolyl isomerase, an enzyme that can affect the activity of ITK (interleukin-2-inducible T-cell kinase).

ACTIVATION-INDUCED CELL DEATH

(AICD). Apoptotic cell death that results from engagement of receptors at the cell surface of a lymphocyte to control clonal expansion. Defects in AICD result in lymphoproliferative disorders.

SMALL INTERFERING RNA

(siRNA). Short double-stranded RNAs of 19–23 nucleotides that induce RNA interference (RNAi), a post-transcriptional process that leads to gene silencing in a sequence-specific manner.

CHEMOKINES

Small, inducibly secreted proteins that induce activation and migration of lymphocytes.

ANTISENSE OLIGONUCLEOTIDES

Short, gene-specific sequences of nucleic acids that are of the opposite strand (complementary) to the targeted mRNA. Classical antisense oligonucleotides target specific strands of RNA within a cell, thereby preventing translation of these RNAs.

ALTERED PEPTIDE LIGANDS

Analogues that are derived from the original antigenic peptide. They commonly have amino-acid substitutions at T-cell receptor (TCR)-contact residues. TCR engagement by these altered peptide ligands usually leads to partial or incomplete T-cell activation. Some of these altered peptide ligands (antagonists) can specifically antagonize and inhibit T-cell activation that is induced by the wild-type antigenic peptide.

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Schwartzberg, P., Finkelstein, L. & Readinger, J. TEC-family kinases: regulators of T-helper-cell differentiation. Nat Rev Immunol 5, 284–295 (2005). https://doi.org/10.1038/nri1591

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