The Tec Family Tyrosine Kinases Itk and Rlk Regulate the Development of Conventional CD8+ T Cells

Atherly, Luana O.; Lucas, Julie Ann; Felices, Martin; Yin, Catherine C.; Reiner, Steven L.; Berg, Leslie J.

doi:10.1016/j.immuni.2006.05.012

Cited by 174 publications

(247 citation statements)

References 54 publications

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“…5B). Interestingly and as shown in Itkand Rlk/Itk-deficient CD8 + T cells [41,42], Eomesodermin mRNA expression was dramatically increased in Dok-1 transgenic CD8 + thymocytes (Fig. 5C).…”

supporting

confidence: 72%

“…The phenotype of CD8 + CD44 high CD122 high T cells in Dok-1 transgenic mice is very similar to that of innate-like CD8 + thymocytes that accumulate in Itk-deficient mice [41,42]. We crossed Dok-1 transgenic mice with SAP-deficient mice to evaluate whether, as shown for Itk −/− mice [43], SAP was required for the development of these innate-like CD8 + T cells.…”

Section: Sap Is Required For the Development Of The Cd8 + Innate-likementioning

confidence: 99%

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Dok‐1 overexpression promotes development of γδ natural killer T cells

et al. 2012

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In T cells, two members of the Dok family, Dok-1 and Dok-2, are predominantly expressed. Recent evidence suggests that they play a negative role in T-cell signaling. In order to define whether Dok proteins regulate T-cell development, we have generated transgenic mice overexpressing Dok-1 in thymocytes and peripheral T cells. We show that overexpression of Dok-1 retards the transition from the CD4 − CD8 − to CD4 + CD8 + stage. Moreover, there is a specific expansion of PLZF-expressing Vγ1.1 + Vδ6.3 + T cells. This subset of γδ T cells acquires innate characteristics including rapid IL-4 production following stimulation and requiring SLAM-associated adaptor protein (SAP) for their development. Moreover, Dok-1 overexpression promotes the generation of an innate-like CD8 + T-cell population that expresses Eomesodermin. Altogether, these findings identify a novel role for Dok-1 in the regulation of thymic differentiation and in particular, in the development of PLZF + γδ T cells.Keywords: γδ T cell r Dok r PLZF r SAP r Thymocyte development Supporting Information available online Introduction αβ T-lymphocyte development is dependent on productive rearrangement of the TCRβ locus and intracellular signaling initiated through the pre-TCR at the CD4 − CD8 − double-negative (DN) stage. Pre-TCR signaling leads to cellular proliferation and progression to the CD4 + CD8 + double-positive (DP) stage where TCRα locus rearrangement is induced. In DP thymocytes, initial TCR signal strength/duration will determine specific gene expression and Correspondence: Dr. Pascale Duplay e-mail: pascale.duplay@iaf.inrs.ca as a consequence will regulate the outcome of thymocyte positive versus negative selection and CD4 versus CD8 lineage differentiation or conventional versus innate lymphocyte lineage choice [1].γδ TCR lymphocytes also develop in the thymus and require productive rearrangement of the TCRγ and δ loci at the DN stage. The strength of TCR signaling is important in controlling αβ/γδ lineage choice. Strong TCR signaling is required for the commitment to the γδ lineage whereas weak TCR signals favor * These authors contributed equally to this work. Eur. J. Immunol. 2012Immunol. . 42: 2491Immunol. -2504 development of αβ lineage cells (reviewed in [2][3][4]). Moreover, TCR signal strength regulates also maturation and acquisition of effector functions in γδ and αβ T-cell development. Therefore, signaling molecules that modulate TCR signal strength play a pivotal role in the regulation of T-cell development and homeostasis. Development signals from the pre-TCR and from the TCR are controlled by the coordinated activity of tyrosine kinases such as Syk-family kinases [5], Src-family kinases [6], and Tec-family kinases [7,8] and adaptor molecules such as , LAT [10], Grb2 [11], and Gads [12].Dok are adaptor proteins that contain a pleckstrin homology domain, a phosphotyrosine binding domain, and a COOHterminal region containing multiple tyrosine phosphorylation sites [13,14]. Dok-1 and Dok-2, the two members of Dok family proteins e...

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“…5B). Interestingly and as shown in Itkand Rlk/Itk-deficient CD8 + T cells [41,42], Eomesodermin mRNA expression was dramatically increased in Dok-1 transgenic CD8 + thymocytes (Fig. 5C).…”

supporting

confidence: 72%

Section: Sap Is Required For the Development Of The Cd8 + Innate-likementioning

confidence: 99%

Dok‐1 overexpression promotes development of γδ natural killer T cells

et al. 2012

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“…It has recently been shown that Tec kinases regulate the development of CD8 ϩ CTLs in this animal model (32,33). Studies of CD8 ϩ T cell function in Itk-deficient mice have reported a disparity between the in vitro responses of these cells and the in vivo responses of these mice to viral infections (30,31).…”

Section: Discussionmentioning

confidence: 96%

Differential Regulation of Human NK Cell-Mediated Cytotoxicity by the Tyrosine Kinase Itk

Khurana

Arneson

Schoon

et al. 2007

The Journal of Immunology

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NK cells are effector lymphocytes that can recognize and eliminate virally infected and transformed cells. NK cells express distinct activating receptors, including an ITAM-containing FcR complex that recognizes Ab-coated targets, and the DNAX-activating protein of 10 kDa-containing NKG2D receptor complex that recognizes stress-induced ligands. The regulatory role of specific tyrosine kinases in these pathways is incompletely understood. In this study, we show that, in activated human NK cells, the tyrosine kinase IL-2-inducible T cell kinase (Itk), differentially regulates distinct NK-activating receptors. Enhanced expression of Itk leads to increases in calcium mobilization, granule release, and cytotoxicity upon stimulation of the ITAM-containing FcR, suggesting that Itk positively regulates FcR-initiated cytotoxicity. In contrast, enhanced Itk expression decreases cytotoxicity and granule release downstream of the DNAX-activating protein of 10 kDa-containing NKG2D receptor, suggesting that Itk is involved in a pathway of negative regulation of NKG2D-initiated granule-mediated killing. Using a kinase mutant, we show that the catalytic activity of Itk is required for both the positive and negative regulation of these pathways. Complementary experiments where Itk expression was suppressed also showed differential regulation of the two pathways. These findings suggest that Itk plays a complex role in regulating the functions initiated by distinct NK cell-activating receptors. Moreover, understanding how these pathways may be differentially regulated has relevance in the setting of autoimmune diseases and antitumor immune responses where NK cells play key regulatory roles.

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“…Recently, we found aberrantly high expression of eomesodermin in CD8 ϩ thymocytes and T cells from Itk Ϫ/Ϫ and Itk/Rlk Ϫ/Ϫ mice (37). Therefore, we also examined Itk Ϫ/Ϫ and Itk/Rlk Ϫ/Ϫ NKT cells for eomesodermin mRNA expression.…”

Section: Tec Family Kinase-deficient Nkt Cells Show Impaired Survivalmentioning

confidence: 98%

“…Although Itk and Rlk are dispensable for the development of CD8 ϩ innate T cells (37)(38)(39), the role of Tec family kinases has not been thoroughly studied in other subsets of innate T cells, such as NKT cells. One previous study demonstrated a role for Itk in NKT cell development, indicating impaired progression of Itk Ϫ/Ϫ NKT cells to stage 3 and a resulting decrease in NKT cell numbers (40).…”

mentioning

confidence: 99%

The Tec Kinases Itk and Rlk Regulate NKT Cell Maturation, Cytokine Production, and Survival

Felices

Berg

2008

The Journal of Immunology

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The Tec kinases Itk and Rlk are required for efficient positive selection of conventional CD4+ and CD8+ T cells in the thymus. In contrast, recent studies have shown that these Tec kinases are dispensable for the development of CD8+ T cells with characteristics of innate T cells. These findings raise questions about the potential role of Itk and Rlk in NKT cell development, because NKT cells represent a subset of innate T cells. To address this issue, we examined invariant NKT cells in Itk−/− and Itk/Rlk−/− mice. We find, as has been reported previously, that Itk−/− mice have reduced numbers of NKT cells with a predominantly immature phenotype. We further show that this defect is greatly exacerbated in the absence of both Itk and Rlk, leading to a 7-fold reduction in invariant NKT cell numbers in the thymus of Itk/Rlk−/− mice and a more severe block in NKT cell maturation. Splenic Itk−/− and Itk/Rlk−/− NKT cells are also functionally defective, because they produce little to no cytokine following in vivo activation. Tec kinase-deficient NKT cells also show enhanced cell death in the spleen. These defects correlate with greatly diminished expression of CD122, the IL-2R/IL-15R β-chain, and impaired expression of the T-box transcription factor, T-bet. These data indicate that the Tec kinases Itk and Rlk provide important signals for terminal maturation, efficient cytokine production, and peripheral survival of NKT cells.

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The Tec Family Tyrosine Kinases Itk and Rlk Regulate the Development of Conventional CD8+ T Cells

Cited by 174 publications

References 54 publications

Dok‐1 overexpression promotes development of γδ natural killer T cells

Dok‐1 overexpression promotes development of γδ natural killer T cells

Differential Regulation of Human NK Cell-Mediated Cytotoxicity by the Tyrosine Kinase Itk

The Tec Kinases Itk and Rlk Regulate NKT Cell Maturation, Cytokine Production, and Survival

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