Cutting Edge: Itk-Dependent Signals Required for CD4+ T Cells to Exert, but Not Gain, Th2 Effector Function

Au-Yeung, Byron B; Katzman, Shoshana D.; Fowell, Deborah J.

doi:10.4049/jimmunol.176.7.3895

Cited by 59 publications

(79 citation statements)

References 25 publications

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“…ϩ T cells at least, such transcriptional enhancement is critical for effective IL-4 production by Th2 cells (29). For IL-4 therefore, NKT cells and conventional Th2 cells share a common requirement for Itk to exert effector function.…”

Section: Discussionmentioning

confidence: 99%

“…IL-4 production can be restored in Itk-deficient Th2 effector cells by the provision of TCR signals with ionomycin (29). This result suggested that conventional CD4 ϩ T cells differentiated into Th2 cells with similar cytokine potential as WT cells but lack the appropriate activation signals to exert effector function.…”

Section: Distinct Roles For Itk In Nkt Cell Development and Effector mentioning

confidence: 92%

“…APC cultures with ␣GalCer in the absence of NKT cells yielded Ͻ5 IFN-␥ spots and Ͻ4 IL-4 spots. The cytokine secretion assay (Miltenyi Biotec) was performed as previously described (29). Briefly, splenocytes from vehicle or ␣GalCer-treated mice were incubated directly ex vivo in the presence or absence of ionomycin (1 g/ml; Calbiochem) for 4 h. After this incubation period, cells were washed and labeled with a bispecific "catch reagent" and incubated for 45 min at 37 o C. Cells were washed and IL-4 and IFN-␥ were detected with PE-conjugated Abs.…”

Section: Cytokine Measurementsmentioning

confidence: 99%

“…ϩ effector cells that in turn was critical for optimal cytokine production (29). Resting NKT cells express cytokine transcripts at a similar level to resting differentiated Th1 and Th2 cells (4), but it is unclear how much these existing transcripts contribute to cytokine protein production on Ag stimulation.…”

Section: Th2-primed Cd4mentioning

confidence: 99%

“…Upon further analysis of the itk Ϫ/Ϫ phenotype, it was shown that under Th2-polarizing conditions, the kinetics and magnitude of IL-4, IL-5, IL-13, and GATA-3 transcript up-regulation during Th2 priming are similar in WT and itk Ϫ/Ϫ cells, suggesting that Itk is not required for early Th2 differentiation steps and Th2 lineage commitment. However, upon a secondary TCR stimulation, Th2-primed itk Ϫ/Ϫ cells fail to enhance IL-4 transcript levels, correlating with severe defects in IL-4 protein production both in vitro and in vivo (29). Thus, Itk appears to be required for the implementation, rather than acquisition of Th2 effector function.…”

mentioning

confidence: 99%

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A Key Role for Itk in Both IFNγ and IL-4 Production by NKT Cells

Au-Yeung

Fowell

2007

The Journal of Immunology

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NKT cells rapidly secrete cytokines upon TCR stimulation and thus may modulate the acquired immune response. Recent studies suggest that signaling for development and effector function in NKT cells may differ from conventional T cells. The tyrosine kinase Itk is activated downstream of the TCR, and its absence in CD4+ T cells results in impaired Th2, but not Th1 responses. In this study, we investigated NKT cell function in the absence of Itk as impaired type 2 responses in vivo could be manifest through IL-4 defects in a number of cell types. We show that Itk-deficient NKT cells up-regulate IL-4 mRNA in the thymus and express constitutive IL-4 and IFN-γ transcripts in peripheral organs. Thus, Itk is not required for the developmental activation of cytokine loci in NKT cells. Nevertheless, Itk-deficient NKT cells are severely impaired in IL-4 protein production. Strikingly, unlike conventional CD4+ T cells, Itk-deficient NKT cells also have profound defects in IFN-γ production. Furthermore, both IL-4 and IFN-γ production were markedly impaired following in vivo challenge with α-galactosyl ceramide. Function can be restored in Itk-deficient NKT cells by provision of calcium signals using ionomycin. These results suggest that NKT cells are highly dependent on Itk for IL-4- and IFN-γ-mediated effector function. Thus, the pattern of cytokine genes that are affected by Itk deficiency appears to be cell lineage-specific, likely reflecting differences in activation threshold between immune effectors. The severe defect in NKT cell function may underlie a number of the Th1 and Th2 immune defects in Itk-deficient mice.

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Section: Discussionmentioning

confidence: 99%

Section: Distinct Roles For Itk In Nkt Cell Development and Effector mentioning

confidence: 92%

Section: Cytokine Measurementsmentioning

confidence: 99%

Section: Th2-primed Cd4mentioning

confidence: 99%

mentioning

confidence: 99%

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A Key Role for Itk in Both IFNγ and IL-4 Production by NKT Cells

Au-Yeung

Fowell

2007

The Journal of Immunology

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Membrane microdomain organization, calcium signal, and NFAT activation as an important axis in polarized Th cell function

et al. 2012

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T helper lymphocytes become polarized upon antigen and cytokine stimuli received after their maturation in the thymus. Since the balance of Th1 and Th2 responses is critical in healthy and pathological immune responses, understanding the molecular base of T cell polarization still remained an important question. Using our Th0/Th1/ Th2 hybridoma model system, we performed a comparative study on polarized Th1 and Th2 cells in terms of their membrane raft expression/composition, their TCR mediated activation signaling, and sensitivity to activation-induced cell death (AICD) using flow and image cytometric methods. We show here that the TCR stimulation induced more intense and sustained Ca 21 -response in Th1 cells compared to Th2 ones correlates well with a shorter nuclear residence time of the Ca 21 -dependent NFAT transcription factor in Th2 cells. In addition, NFAT translocation directly depended on lipid raft integrity/membrane cholesterol level. Expression pattern of raftophilic accessory proteins (CD4, CD59, and CD48) and lipids (GM1, cholesterol) were also different in the Th1 and Th2 hybridomas, similarly to differentiated spleen Th cells. The activationinduced, remarkably clustered and polarized membrane distribution of TCR/CD3 complex in Th1, but not in Th2 cells, together with an increased raft localization of Kv1.3 ion channels regulating the Ca 21 -response, are consistent with the above properties of NFAT. Finally, the polarized Th cells, especially Th1, were more sensitive to AICD than their unpolarized Th0 precursor. These results suggest that the membrane microdomain organization-Ca 21 -signaling-NFAT activation axis is an important determinant of polarized Th cell effector function and fate. ' 2012 International Society for Advancement of Cytometry

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Memory phenotype CD8⁺ T cells with innate function selectively develop in the absence of active Itk

Sahu

Walsh

et al. 2007

Eur J Immunol

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T cells with a memory-like phenotype and possessing innate immune function have been previously identified as CD8(+)CD44(hi) cells. These cells rapidly secrete IFN-gamma upon stimulation with IL-12/IL-18 and are involved in innate responses to infection with Listeria monocytogenes. The signals regulating these cells are unclear. The Tec kinase Itk regulates T cell activation and we report here that a majority of the CD8(+) T cells in Itk null mice have a phenotype of CD44(hi) similar to memory-like innate T cells. These cells are observed in mice carrying an Itk mutant lacking the kinase domain, indicating that active Tec kinase signaling suppresses their presence. These cells carry preformed message for and are able to rapidly produce IFN-gamma upon stimulation in vitro with IL-12/IL-18, and endow Itk null mice the ability to effectively respond to infection with L. monocytogenes or exposure to lipopolysaccharides by secretion of IFN-gamma. Transfer of these cells rescues the ability of IFN-gamma null mice to reduce bacterial burden following L. monocytogenes infection, indicating that these cells are functional CD8(+)CD44(hi) T cells previously detected in vivo. These results indicate that active signals from Tec kinases regulate the development of memory-like CD8(+) T cells with innate function.

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Cutting Edge: Itk-Dependent Signals Required for CD4+ T Cells to Exert, but Not Gain, Th2 Effector Function

Cited by 59 publications

References 25 publications

A Key Role for Itk in Both IFNγ and IL-4 Production by NKT Cells

A Key Role for Itk in Both IFNγ and IL-4 Production by NKT Cells

Membrane microdomain organization, calcium signal, and NFAT activation as an important axis in polarized Th cell function

Memory phenotype CD8⁺ T cells with innate function selectively develop in the absence of active Itk

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Cutting Edge: Itk-Dependent Signals Required for CD4+ T Cells to Exert, but Not Gain, Th2 Effector Function

Cited by 59 publications

References 25 publications

A Key Role for Itk in Both IFNγ and IL-4 Production by NKT Cells

A Key Role for Itk in Both IFNγ and IL-4 Production by NKT Cells

Membrane microdomain organization, calcium signal, and NFAT activation as an important axis in polarized Th cell function

Memory phenotype CD8+ T cells with innate function selectively develop in the absence of active Itk

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Memory phenotype CD8⁺ T cells with innate function selectively develop in the absence of active Itk