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

Felices, Martin; Berg, Leslie J.

doi:10.4049/jimmunol.180.5.3007

Cited by 105 publications

(138 citation statements)

References 64 publications

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“…High TCR avidity for self ligands has long been proposed as a critical factor for the development of NKT cells (53). Consistent with this hypothesis was the finding that ITK-deficient and SLP76:Y145F mutant mice, which have reduced TCR signaling capacities, have significant defects in NKT cell development (54,55). Furthermore, PMA plus ionomycin stimulation of DP thymocytes followed by 5 d in culture with OP9-dl1 cells was shown to induce PLZF in gd T cells (18).…”

Section: Discussionsupporting

confidence: 64%

PLZF Induces the Spontaneous Acquisition of Memory/Effector Functions in T Cells Independently of NKT Cell-Related Signals

Kovalovsky

Alonzo

Uche

et al. 2010

The Journal of Immunology

102

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The broad complex, tramtrack, bric-a-brac–zinc finger (BTB-ZF) transcription factor promyelocytic leukemia zinc finger (PLZF) is required for development of the characteristic innate/effector functions of NKT cells. In this study, we report the characterization and functional analysis of transgenic mouse T cells with forced expression of PLZF. PLZF expression was sufficient to provide some memory/effector functions to T cells without the need for Ag stimulation or proliferation. The acquisition of this phenotype did not require the proliferation typically associated with T cell activation. Furthermore, PLZF transgenic cells maintained a diverse TCR repertoire, indicating that there was no preferential expansion of specific clones. Functionally, PLZF transgenic CD4 and CD8 lymphocytes were similar to wild type memory cells, in that they had similar requirements for costimulation and exhibited a similar pattern of cytokine secretion, with the notable exception that transgenic T cells produced significantly increased levels of IL-17. Whereas transgene-mediated PLZF expression was not sufficient to rescue NKT cell development in Fyn- or signaling lymphocytic activation-associated protein (SAP)-deficient mice, the acquisition of memory/effector functions induced by PLZF in conventional T cells was independent of Fyn and SAP. These data show that PLZF is sufficient to promote T cell effector functions and that PLZF acts independently of SAP- and Fyn-mediated signaling pathways.

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Section: Discussionsupporting

confidence: 64%

PLZF Induces the Spontaneous Acquisition of Memory/Effector Functions in T Cells Independently of NKT Cell-Related Signals

Kovalovsky

Alonzo

Uche

et al. 2010

The Journal of Immunology

102

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“…These proteins are important mediators of antigen receptor signaling in lymphocytes, and ITK is believed to be the predominant TEC kinase in T cells and one of the key molecules involved in NKT cell maturation and survival. [17][18][19][20][21] Our report, and the previous report of ITK deficiency, reveals a different clinical spectrum from that of classical XLP. First, while in XLP the predominant lymphoproliferation is Burkitt's lymphoma, 4 out of 5 published patients with ITK deficiency had Hodgkin's disease.…”

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confidence: 65%

IL-2-inducible T-cell kinase deficiency: clinical presentation and therapeutic approach

Stepensky¹,

Weintraub²,

Yanir³

et al. 2010

Haematologica

101

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Homozygocity mappingWe searched for homozygous regions in the DNA samples of subjects IV-4 and IV-3 using GeneChip Human Mapping 250K NspI Array of Affymetrix. The chip allows genotyping of SNPs with an average distance of approximately 50 kb between the markers. Digestion with NspI, ligation of the adaptors, and amplification with generic primers that recognize the adaptor sequence were followed by fragmentation, end labeling, and hybridization to the chip in accordance with the manufacturer's instructions. Homozygous regions greater than 5.0 Mb were manually detected. 15 Mutation analysisMutation analysis was performed by direct sequencing of PCR fragments obtained after nested amplification of the exonic and flanking intronic region coding sequences of ITK 17 exons. Primers to amplify the genomic DNA samples were designed according to GenBank sequences. Direct cycle sequencing of all PCR fragments was performed with BigDye Terminator v3.1 cycle sequencing kit (Applied Biosystems) and analyzed by capillary electrophoresis on an ABI Prism 3130 Genetic Analyzer (Applied Biosystems). Analyzed sequences were compared with the cDNA and genomic DNA sequences in GenBank accession numbers NM_005546 (human ITK mRNA). Constructs and immunoblot analyses Results and Discussion Clinical phenotypeThe family tree and a clinical summary of the affected family are presented in Figure 1A and Table 1. Subject IV-5 presented at the age of 4.5 years with fever, lymphadenopathy and splenomegaly. Her past history was significant for recurrent febrile episodes which had started at four years of age. Lymph node biopsy revealed Hodgkin's lymphoma, CD30+ and EBV-LMP + and CD20-. She was treated with a regimen for advanced stage Hodgkin's disease with a good response. Four months off IL-2-inducible T-cell kinase deficiency haematologica | 2011; 96(3) 473 therapy she presented with fever, skin rash, lung disease, splenomegaly, trilineage cytopenia, hypertriglyceridemia, hypofibrinogenemia and hyperferritinemia. Bone marrow evaluation showed hemophagocytosis with Hodgkin cells positive for CD20, CD30 and EBV-LMP. Serum EBV PCR showed 125,850 copies/mL and positive EBNA IgG.Immunoglobulins were low (IgG 463 mg/dL, undetectable IgA and IgM). She was diagnosed with relapsed Hodgkin's lymphoma and hemophagocytic lymphohistiocytosis. Therapy with steroids, rituximab and chemotherapy (VP-16, vinorelbine and gemcitabine) was started but she developed further disease progression with respiratory failure and died. Subject IV-3 presented at five years of age with fever and lymphadenopathy. His past history included a profound sensorineural hearing defect, mild mental retardation and recurrent infections. Laboratory tests showed hypogammaglobulinemia (IgG 291 mg/dL, IgA and IgM below 42 and 32, respectively), positive anti-EBV VCA IgG, and negative anti-EBNA. EBV PCR was not carried out. A lymph node biopsy showed mixed cellularity Hodgkin's lymphoma with numerous Hodgkin's cells and few CD30 positive and CD20 negative Reed-Sternberg cells...

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“…Cells used for quantitative PCR were stimulated for 10 and 20 hours and examined for IL-4 and IFN␥ mRNA. For intracellular cytokine staining, cells from WT and Itk Ϫ/Ϫ mice were stimulated as previously described (6). Cells were then surface stained for anti-TCR␥ and anti-NK1.1, fixed, and permeabilized using a Cytofix/Cytoperm kit (BD Pharmingen) and stained for IL-4 and IFN␥.…”

Section: Methodsmentioning

confidence: 99%

Tec kinase Itk in γδT cells is pivotal for controlling IgE production in vivo

Felices

Yin

Kosaka

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

114

145

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T cell development ͉ T cell differentiation ͉ T cell signaling T he Tec family tyrosine kinase Itk is important for signaling downstream of the T cell receptor (1). In particular, Itkdeficient T cells have defects in phospholipase C-␥ (PLC-␥) phosphorylation, calcium mobilization, mitogen-activated protein kinase (MAP kinase) activation, and AP-1 and nuclear factor of activated T cells (NFAT) activation after T cell receptor (TCR) stimulation. Itk is also critical for conventional ␣␤ T cell development, selection, and function. Of particular importance, Itk signaling regulates CD4 ϩ T helper cell differentiation, playing a key role in the development of Th2 responses (2). Based on this welldocumented defect of Itk Ϫ/Ϫ mice in generating Th2 effector responses and cytokine production, it was surprising to discover that these mice had spontaneously elevated levels of serum IgE (3, 4), as B cell isotype switching to IgE is highly dependent on Th2 cytokines IL-4 and IL-13 (5). As our previous studies had indicated that Itk Ϫ/Ϫ ␣␤ TCR ϩ NKT cells (referred to as ␣␤ NKT cells) were also highly defective in producing effector cytokines such as IL-4 (6), we considered the possibility that ␥␦ TCR ϩ NKT cells were the major source of Th2 cytokines in Itk Ϫ/Ϫ mice.The ␥␦ T cells are a highly conserved subset of T cells that constitutes 1-5% of the lymphocytes in the blood and peripheral organs of mice but can account for up to 50% of the lymphocytes in the mucosal epithelia. As with other subsets of ''innate'' T cells, ␥␦ T cells express memory cell surface markers (7), and are capable of rapidly secreting effector cytokines (8). Among the many functions attributed to ␥␦ T cells, a great deal of recent interest has focused on their ability to modulate adaptive immune responses, specifically the humoral response (9).A variety of studies have indicated that ␥␦ T cells are able to provide help for B cell responses. Initial studies performed in mice lacking ␣␤ T cells showed that B cell expansion, differentiation, and secretion of 'T-dependent' antibody isotypes, IgE, and IgG 1 , were all intact in these mice (10). Furthermore, TCR␤ Ϫ/Ϫ mice challenged repeatedly with parasitic infections could produce germinal centers and generate increased antibody production (11). Using a model of pulmonary allergic inflammation, decreased production of IgE and IgG 1 was seen in mice lacking ␥␦ T cells compared with WT mice (12). The ␥␦ T cells have also been shown to directly induce germinal center formation and Ig hypermutation (13). Interestingly, even though the ␥␦ T cells expressing CD4 account for only 5-10% of all ␥␦ cells, it is this subset that appears to be responsible for inducing germinal centers (14). Human ␥␦ T cells have also been found in germinal centers; these cells were found to up-regulate B cell costimulatory molecules such as CD40L, OX40, CD70, and inducible costimulatory molecule (ICOS) in response to TCR stimulation (15, 16). Together, these data indicate that ␥␦ T cells can promote, either directly or indirectly, th...

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

Cited by 105 publications

References 64 publications

PLZF Induces the Spontaneous Acquisition of Memory/Effector Functions in T Cells Independently of NKT Cell-Related Signals

PLZF Induces the Spontaneous Acquisition of Memory/Effector Functions in T Cells Independently of NKT Cell-Related Signals

IL-2-inducible T-cell kinase deficiency: clinical presentation and therapeutic approach

Tec kinase Itk in γδT cells is pivotal for controlling IgE production in vivo

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