Itk Signals Promote Neuroinflammation by Regulating CD4<sup>+</sup>T-Cell Activation and Trafficking

Kannan, A.; Kim, Do Geun; August, Avery; Bynoe, Margaret S.

doi:10.1523/jneurosci.1957-14.2015

Cited by 35 publications

(28 citation statements)

References 65 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Despite relatively normal number (trending the lower range) of CD8 + αβ T cells, Itk −/− mice exhibited CD4 + αβ T-cell lymphopenia, with reduced proportion of naive and increased memory αβ T cells (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31). In the absence of Itk, mouse CD4 + T cells are impaired in Th2 (producing IL-4/5/13) (32)(33)(34)(35)(36)(37)(38), Th9 (producing IL-9) (39), Th17 (producing IL-17) (35,(40)(41)(42), and Tr1 (producing IL-10) cell responses (43), while they are enhanced in Th1 (producing IFN-γ) cell response (32,34,38,44,45). Analysis of Itk −/− mice also reveals altered γδ T-cell development (46)(47)(48)(49); however, the presence and function of γδ T cells has not been evaluated in ITKdeficient humans.…”

Section: Introductionmentioning

confidence: 99%

Interleukin-2-Inducible T-Cell Kinase Deficiency Impairs Early Pulmonary Protection Against Mycobacterium tuberculosis Infection

Huang

McGee

et al. 2020

Front. Immunol.

View full text Add to dashboard Cite

Interleukin-2 (IL-2) inducible T-cell kinase (ITK) is a non-receptor tyrosine kinase highly expressed in T-cell lineages and regulates multiple aspects of T-cell development and function, mainly through its function downstream of the T-cell receptor. Itk deficiency can lead to CD4 lymphopenia and Epstein-Bar virus (EBV)-associated lymphoproliferation and recurrent pulmonary infections in humans. However, the role of the ITK signaling pathway in pulmonary responses in active tuberculosis due to Mtb infection is not known. We show here that human lungs with active tuberculosis exhibit altered T-cell receptor/ITK signaling and that Itk deficiency impaired early protection against Mtb in mice, accompanied by defective development of IL-17A-producing γδ T cells in the lungs. These findings have important implications of human genetics associated with susceptibility to Mtb due to altered immune responses and molecular signals modulating host immunity that controls Mtb activity. Enhancing ITK signaling pathways may be an alternative strategy to target Mtb infection, especially in cases with highly virulent strains in which IL-17A plays an essential protective role.

show abstract

Section: Introductionmentioning

confidence: 99%

Interleukin-2-Inducible T-Cell Kinase Deficiency Impairs Early Pulmonary Protection Against Mycobacterium tuberculosis Infection

Huang

McGee

et al. 2020

Front. Immunol.

View full text Add to dashboard Cite

show abstract

“…ITK regulates the differentiation of naive CD4 + T cells into various Th cell subsets (4)(5)(6)(7)(8) and is required for effector T cell responses that protect against certain infections, as well as those that contribute to allergic and autoimmune responses (4,7,(9)(10)(11). ITK has also been implicated in CD4 + T cell trafficking to nonlymphoid tissues, such as colon and brains, in two different experimental disease models (12,13). However, the role of ITK in CD8 + T cell trafficking, and in particular, trafficking to the intestine, has not been closely examined.…”

Section: Introductionmentioning

confidence: 99%

CD8+ T Cells Require ITK-Mediated TCR Signaling for Migration to the Intestine

Cho

Shin

et al. 2020

ImmunoHorizons

View full text Add to dashboard Cite

The Tec kinase IL-2-inducible T cell kinase (ITK) regulates the expression of TCR-induced genes. Itk 2/2 T cell responses are impaired but not absent. ITK inhibition prevented colitis disease progression and impaired T cell migration to the colon in mice. To examine the function of ITK in T cell migration to the intestine, we examined the number of gut T cells in Itk 2/2 mice and then evaluated their expression of gut-homing receptors. Combined with in vitro murine T cell stimulation and in vivo migration assay using congenic B6 mice, we demonstrated an essential role for ITK in T cell migration to the intestine in mice. Reconstitution of Itk 2/2 mouse CD8 + T cells with IFN regulatory factor 4 restored gut-homing properties, providing mechanistic insight into the function of ITK-mediated signaling in CD8 + T cell migration to the intestinal mucosa in mice. ImmunoHorizons, 2020, 4: 57-71.

show abstract

“…ITK has a well-established role in Th2 mediated inflammation, but reports are conflicting on its role in Th1 effector function [5, 7, 9, 19-21]. While some data indicate that ITK positively regulates Th1 development and effector function in mouse T cells [7, 9, 20, 21], our data suggest that ITK is dispensable for Th1 effector function in primary human T cells, and that targeting ITK alone is therefore unlikely to be broadly immunosuppressive.…”

Section: Discussionmentioning

confidence: 99%

A negative role for the interleukin-2-inducible T-cell kinase (ITK) in human Foxp3+ T_REG differentiation

Mamontov

Eberwine

Perrigoue

et al. 2018

Preprint

View full text Add to dashboard Cite

26The Tec kinases ITK (interleukin-2-inducible T-cell kinase) and RLK (resting lymphocyte kinase) are critical 27 components of the proximal TCR/CD3 signal transduction machinery, and data in mice suggest that ITK 28 negatively regulates TREG differentiation. However, whether Tec kinases modulate TREG development 29 and/or function in human T cells remains unknown. Using a novel self-delivery siRNA platform (sdRNA), 30we found that ITK knockdown in primary human naïve peripheral blood CD4 T cells increased Foxp3 + TREG 31 differentiation under both TREG and T effector (Teff) cell priming conditions. ITK knockdown also 32 enhanced the expression of the co-inhibitory receptor PD-1 on FoxP3+ T cells. TREGS differentiated in 33 vitro (iTREG) after ITK knockdown displayed suppressive capacity against effector CD4+ T cell 34 proliferation. ITK knockdown decreased IL-17A production in T cells primed under Th17 conditions and 35 increased Th1 differentiation. Finally, a dual ITK/RLK Tec kinase inhibitor blocked TREG differentiation and 36 T cell activation in general. Our data suggest that targeting ITK in human T cells may be an effective 37 approach to boost TREG in the context of autoimmune diseases, but non-specific inhibition of other Tec 38 family kinases may broadly inhibit T cell activation. 39 40 41

show abstract

Itk Signals Promote Neuroinflammation by Regulating CD4⁺T-Cell Activation and Trafficking

Cited by 35 publications

References 65 publications

Interleukin-2-Inducible T-Cell Kinase Deficiency Impairs Early Pulmonary Protection Against Mycobacterium tuberculosis Infection

Interleukin-2-Inducible T-Cell Kinase Deficiency Impairs Early Pulmonary Protection Against Mycobacterium tuberculosis Infection

CD8+ T Cells Require ITK-Mediated TCR Signaling for Migration to the Intestine

A negative role for the interleukin-2-inducible T-cell kinase (ITK) in human Foxp3+ T_REG differentiation

Contact Info

Product

Resources

About

Itk Signals Promote Neuroinflammation by Regulating CD4+T-Cell Activation and Trafficking

Cited by 35 publications

References 65 publications

Interleukin-2-Inducible T-Cell Kinase Deficiency Impairs Early Pulmonary Protection Against Mycobacterium tuberculosis Infection

Interleukin-2-Inducible T-Cell Kinase Deficiency Impairs Early Pulmonary Protection Against Mycobacterium tuberculosis Infection

CD8+ T Cells Require ITK-Mediated TCR Signaling for Migration to the Intestine

A negative role for the interleukin-2-inducible T-cell kinase (ITK) in human Foxp3+ TREG differentiation

Contact Info

Product

Resources

About

Itk Signals Promote Neuroinflammation by Regulating CD4⁺T-Cell Activation and Trafficking

A negative role for the interleukin-2-inducible T-cell kinase (ITK) in human Foxp3+ T_REG differentiation