Itk-mediated integration of T cell receptor and cytokine signaling regulates the balance between Th17 and regulatory T cells

Gómez-Rodríguez, Julio; Wohlfert, Elizabeth A.; Handon, Robin; Meylan, Françoise; Wu, Jing; Anderson, Stacie M.; Kirby, Martha; Belkaid, Yasmine; Schwartzberg, Pamela L.

doi:10.1084/jem.20131459

Cited by 153 publications

(204 citation statements)

References 60 publications

(90 reference statements)

Supporting

Mentioning

186

Contrasting

Unclassified

Order By: Relevance

“…This is consistent with early studies with ITK knock-out mice that show that Th2-and IL-4-dependent disease processes, such as ovalbumin-induced asthma, are blocked by ITK deletion, whereas Th1 responses remain intact, presumably due to redundancy of RLK signaling (14,48). RLK expression in Th17 cells is not well studied, but mice that have deletions of both kinases show profound defects in Th17 differentiation and function, a finding that was confirmed in our studies using human Th17 cells (9). Thus, combined inhibition of ITK and RLK would be expected to target both Th1 and Th17 cell differentiation and function.…”

Section: Discussionsupporting

confidence: 82%

“…This could be an optimal therapeutic combination, given the importance of these two T helper cell subsets in the development of autoimmune diseases such as psoriasis, psoriatic arthritis, inflammatory bowel disease, and rheumatoid arthritis (49 -56). Interestingly, recent data utilizing ITK knock-out mice indicate that along with the decrease in Th17 cell differentiation and function, there is an increase in Treg cells that function in suppres- sion of disease in a murine adoptive transfer model of colitis (9). Thus, an added value of regulating the pathways targeted by PRN694 is potentially an increase in regulatory T-cells that also are important in control of autoimmune disease.…”

Section: Discussionmentioning

confidence: 99%

“…The Th2 deficiency initiated interest in ITK as a therapeutic target in asthma, because Itk Ϫ/Ϫ mice are resistant to ovalbumin-induced asthma (8). More recently, attention has shifted to autoimmune disease because of the effects of ITK deletion on Th17 function and the concomitant increase in regulatory T-cell (Treg) numbers and function (9). The clinical target validation of IL-17 in psoriasis and psoriatic arthritis adds additional support to the notion that ITK could be a relevant therapeutic target in these diseases (10).…”

Section: Interleukin-2-inducible T-cell Kinase (Itk) and Resting Lympmentioning

confidence: 99%

See 2 more Smart Citations

Targeting Interleukin-2-inducible T-cell Kinase (ITK) and Resting Lymphocyte Kinase (RLK) Using a Novel Covalent Inhibitor PRN694

Zhong

Dong

Strattan

et al. 2015

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: ITK and RLK are unique to effector lymphocytes and critical for immune activation. Results: A novel selective covalent ITK/RLK inhibitor called PRN694 was discovered, which blocks T-cell and NK cell activation. Conclusion: PRN694 provides an effective tool to elucidate the roles of ITK and RLK in immune cell signaling. Significance: PRN694 could be an effective therapy for T-cell-or NK cell-driven autoimmune, inflammatory, and malignant diseases.

show abstract

Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Section: Interleukin-2-inducible T-cell Kinase (Itk) and Resting Lympmentioning

confidence: 99%

See 1 more Smart Citation

Targeting Interleukin-2-inducible T-cell Kinase (ITK) and Resting Lymphocyte Kinase (RLK) Using a Novel Covalent Inhibitor PRN694

Zhong

Dong

Strattan

et al. 2015

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…This cluster included three genes that were previously described in the context of Treg development and function (Fig. 4A): Pde3b, Satb1, and Itk (38)(39)(40). This cluster also contained Tcf7, which was one of the most strongly underrepresented proteins in Tregs (Supplemental Table I).…”

Section: Expression Of the Transcription Factor Tcf7 In Tregsmentioning

confidence: 81%

Transcription Factor 7 Limits Regulatory T Cell Generation in the Thymus

Barra

Richards

Hansson

et al. 2015

The Journal of Immunology

View full text Add to dashboard Cite

Regulatory T cells (Tregs) differentiate in the thymus, but the mechanisms that control this process are not fully understood. We generated a comprehensive quantitative and differential proteome of murine Tregs and conventional T cells. We identified 5225 proteins, 164 of which were differentially expressed in Tregs. Together with the comparative analysis of proteome and gene expression data, we identified TCF7 as a promising candidate. Genetic elimination of transcription factor 7 (TCF7) led to increased fractions of Tregs in the thymus. Reduced levels of TCF7, found in the heterozygote, resulted in a greater potential for Treg precursors to differentiate into the Treg lineage. In contrast, activation of TCF7 through β-catenin had the opposite effect. TCF7 levels influenced the required TCR signaling strength of Treg precursors, and TCF7 deficiency broadened the repertoire and allowed lower TCR affinities to be recruited into the Treg lineage. FOXP3 was able to repress TCF7 protein expression. In summary, we propose a regulatory role for TCF7 in limiting access to the Treg lineage.

show abstract

“…It was also shown that ITK deletion affects the function of Th17 cells and that there is an increase in regulatory T cell (Treg) numbers and function in the absence of this kinase. This makes ITK a promising drug target for autoimmune disorders 50, 51. It was also found that in human NK cells ITK plays a role in regulating cell‐mediated cytotoxicity 52.…”

Section: Tec Family Kinasesmentioning

confidence: 98%

Targets for Ibrutinib Beyond B Cell Malignancies

et al. 2015

View full text Add to dashboard Cite

Ibrutinib (Imbruvica™) is an irreversible, potent inhibitor of Bruton's tyrosine kinase (BTK). Over the last few years, ibrutinib has developed from a promising drug candidate to being approved by FDA for the treatment of three B cell malignancies, a truly remarkable feat. Few, if any medicines are monospecific and ibrutinib is no exception; already during ibrutinib's initial characterization, it was found that it could bind also to other kinases. In this review, we discuss the implications of such interactions, which go beyond the selective effect on BTK in B cell malignancies. In certain cases, the outcome of ibrutinib treatment likely results from the combined inhibition of BTK and other kinases, causing additive or synergistic, effects. Conversely, there are also examples when the clinical outcome seems unrelated to inhibition of BTK. Thus, more specifically, adverse effects such as enhanced bleeding or arrhythmias could potentially be explained by different interactions. We also predict that during long‐term treatment bone homoeostasis might be affected due to the inhibition of osteoclasts. Moreover, the binding of ibrutinib to molecular targets other than BTK or effects on cells other than B cell‐derived malignancies could be beneficial and result in new indications for clinical applications.

show abstract

Itk-mediated integration of T cell receptor and cytokine signaling regulates the balance between Th17 and regulatory T cells

Abstract: Loss of the Tec family kinase Itk results in a bias to FoxP3+ Treg cell differentiation and reduced TCR-induced phosphorylation of mTOR targets.

Cited by 153 publications

References 60 publications

Targeting Interleukin-2-inducible T-cell Kinase (ITK) and Resting Lymphocyte Kinase (RLK) Using a Novel Covalent Inhibitor PRN694

Targeting Interleukin-2-inducible T-cell Kinase (ITK) and Resting Lymphocyte Kinase (RLK) Using a Novel Covalent Inhibitor PRN694

Transcription Factor 7 Limits Regulatory T Cell Generation in the Thymus

Targets for Ibrutinib Beyond B Cell Malignancies

Contact Info

Product

Resources

About