A Role for the Tec Family Tyrosine Kinase Txk in T Cell Activation and Thymocyte Selection

Sommers, Connie L.; Rabin, Ronald L.; Grinberg, Alexander; Tsay, Henry C; Farber, Joshua M.; Love, Paul E.

doi:10.1084/jem.190.10.1427

Cited by 61 publications

(50 citation statements)

References 57 publications

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“…Itk and Txk have both been shown to be downstream of the TCR, and to play a role in Ca 2ϩ mobilization, PLC-␥1 phosphorylation and activation, and cytokine (IL-2 and IFN-␥) production (15,16,18). Interestingly, Itk appears to play a more dominant role in these signaling pathways than Txk, as Txk Ϫ/Ϫ T cells showed more modest defects than those observed in T cells from Itk Ϫ/Ϫ or Itk Ϫ/Ϫ /Txk Ϫ/Ϫ mice (17,18). Additional data have suggested that Itk and Txk have different functions in T cell signaling.…”

Section: The Function Of the Tec Kinase In T Cellsmentioning

confidence: 91%

“…Gene-targeting studies first demonstrated that Itk plays a role in TCR signaling leading to IL-2 gene induction, and indicated a role for Itk in the activation of PLC-␥1 leading to calcium mobilization (15,16). More recent studies have suggested that Txk may have a similar function to Itk in T cells (17,18). Additional studies have also suggested a specific role for Itk in the differentiation and function of Th2 effector cells (19) and for Txk in Th1 effector cells (20).…”

Section: S Timulation Of the Tcr On Mature T Cells Induces A Seriesmentioning

confidence: 99%

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Tec Kinase Signaling in T Cells Is Regulated by Phosphatidylinositol 3-Kinase and the Tec Pleckstrin Homology Domain

Yang

Ching

Tsoukas

et al. 2001

The Journal of Immunology

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Tec, the prototypical member of the Tec family of tyrosine kinases, is abundantly expressed in T cells and other hemopoietic cell types. Although the functions of Itk and Txk have recently been investigated, little is known about the role of Tec in T cells. Using antisense oligonucleotide treatment to deplete Tec protein from primary T cells, we demonstrate that Tec plays a role in TCR signaling leading to IL-2 gene induction. Interestingly, Tec kinases are the only known family of tyrosine kinases containing a pleckstrin homology (PH) domain. Using several PH domain mutants overexpressed in Jurkat T cells, we show that the Tec PH domain is required for Tec-mediated IL-2 gene induction and TCR-mediated Tec tyrosine phosphorylation. Furthermore, we show that Tec colocalizes with the TCR after TCR cross-linking, and that both the Tec PH and Src homology (SH) 2 domains play a role in this association. Wortmannin, a phosphatidylinositol 3-kinase inhibitor, abolishes Tec-mediated IL-2 gene induction and Tec tyrosine phosphorylation, and partially suppresses Tec colocalization with the activated TCR. Thus, our data implicate the Tec kinase PH domain and phosphatidylinositol 3-kinase in Tec signaling downstream of the TCR.

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Section: The Function Of the Tec Kinase In T Cellsmentioning

confidence: 91%

Section: S Timulation Of the Tcr On Mature T Cells Induces A Seriesmentioning

confidence: 99%

Tec Kinase Signaling in T Cells Is Regulated by Phosphatidylinositol 3-Kinase and the Tec Pleckstrin Homology Domain

Yang

Ching

Tsoukas

et al. 2001

The Journal of Immunology

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“…CD5 Ϫ/Ϫ mice (16) were obtained from Dr. Ron Schwartz, National Institute of Allergy and Infectious Diseases, National Institutes of Health (Bethesda, MD). TCR-tg mice used in these studies included the MHC class I-restricted TCRs P14 (20) (24).…”

Section: Micementioning

confidence: 99%

“…Thymocyte stimulations, immunoprecipitations, Western blotting, and PAGE were performed as described (24,25). Briefly, thymocytes were incubated for 5 min in medium lacking (Ϫ) or containing (ϩ) pervanadate (1 mM; Sigma).…”

Section: Western Blot Analysismentioning

confidence: 99%

Fine Tuning of TCR Signaling by CD5

Azzam

DeJarnette

Huang

et al. 2001

The Journal of Immunology

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247

273

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Current data indicate that CD5 functions as an inhibitor of TCR signal transduction. Consistent with this role, thymocyte selection in TCR transgenic/CD5−/− mice is altered in a manner suggestive of enhanced TCR signaling. However, the impact of CD5 deletion on thymocyte selection varies depending on the transgenic TCR analyzed, ranging from a slight to a marked shift from positive toward negative selection. An explanation for the variable effect of CD5 on selection is suggested by the observation that CD5 surface expression is regulated by TCR signal intensity during development and CD5 surface levels on mature thymocytes and T cells parallel the avidity of the positively selecting TCR/MHC/ligand interaction. In this study, we generated mice that overexpress CD5 during thymocyte development (CD5-tg), and then examined the effect of CD5 overexpression or CD5 deletion (CD5−/−) on selection of thymocytes that express the same TCR transgenes. The results demonstrate that the effect on thymocyte selection of altering CD5 expression depends on the avidity of the selecting interaction and, consequently, the level of basal (endogenous) CD5 surface expression. Substitution of endogenous CD5 with a transgene encoding a truncated form of the protein failed to rescue the CD5−/− phenotype, demonstrating that the cytoplasmic domain of CD5 is required for its inhibitory function. Together, these results indicate that inducible regulation of CD5 surface expression during thymocyte selection functions to fine tune the TCR signaling response.

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“…[1][2][3][4][5][6][7][8][9][10] Tec, Itk and Txk play important roles in the differentiation and function of T cells. [11][12][13][14][15] Indeed, overexpression of Tec in T cells leads to enhanced gene expression of interleukin (IL)-2 mediated by TCR/CD3 or CD28 stimulation, while the introduction of a kinase dead Tec into T cells suppresses IL-2 gene expression. 11,16) Mice deficient in Itk display moderate impairment of both T cell development and peripheral T cell activation, whereas those deficient in Rlk/Txk show a slight decrease in the number of mature T cells, in particular of the CD4 ϩ subset.…”

mentioning

confidence: 99%