Activation of the Tec Kinase ITK Controls Graded IRF4 Expression in Response to Variations in TCR Signal Strength

Overview

Journal J Immunol

Specialty Allergy & Immunology

Date 2020 Jun 5

PMID 32493815

Citations 14

Authors

James M Conley

Michael P Gallagher

Anjana Rao

Leslie J Berg

Affiliations

Soon will be listed here.

Abstract

TCR signal strength is critical for CD8 T cell clonal expansion after Ag stimulation. Levels of the transcription factor IRF4 control the magnitude of this process through the induction of genes involved in proliferation and glycolytic metabolism. The signaling mechanism connecting graded TCR signaling to the generation of varying amounts of IRF4 is not well understood. In this study, we show that Ag potency regulates the kinetics but not the magnitude of NFAT1 activation in single mouse CD8 T cells. Consequently, T cells that transduce weaker TCR signals exhibit a marked delay in mRNA induction, resulting in decreased overall IRF4 expression in individual cells and increased heterogeneity within the clonal population. We further show that the activity of the tyrosine kinase ITK acts as a signaling catalyst that accelerates the rate of the cellular response to TCR stimulation, controlling the time to onset of gene transcription. These findings provide insight into the function of ITK in TCR signal transduction that ultimately regulates IRF4 expression levels in response to variations in TCR signal strength.

Citing Articles

Spontaneous high clonal expansion of Wilms' tumor gene 1-specific cytotoxic T-lymphocytes in patients with Wilms' tumor gene 1-expressing solid tumor.

Morimoto S, Tanaka Y, Nakata J, Fujiki F, Hasegawa K, Nakajima H Cancer Immunol Immunother. 2024; 74(1):15.

PMID: 39509060 PMC: 11543974. DOI: 10.1007/s00262-024-03862-8.

Single-cell NAD(H) levels predict clonal lymphocyte expansion dynamics.

Turner L, Van Le T, Cross E, Queriault C, Knight M, Trihemasava K Sci Immunol. 2024; 9(93):eadj7238.

PMID: 38489349 PMC: 11064129. DOI: 10.1126/sciimmunol.adj7238.

Cbl-b mitigates the responsiveness of naive CD8 T cells that experience extensive tonic T cell receptor signaling.

Eggert J, Zinzow-Kramer W, Hu Y, Kolawole E, Tsai Y, Weiss A Sci Signal. 2024; 17(822):eadh0439.

PMID: 38319998 PMC: 10897907. DOI: 10.1126/scisignal.adh0439.

Antigen perception in T cells by long-term Erk and NFAT signaling dynamics.

Wither M, White W, Pendyala S, Leanza P, Fowler D, Kueh H Proc Natl Acad Sci U S A. 2023; 120(52):e2308366120.

PMID: 38113261 PMC: 10756264. DOI: 10.1073/pnas.2308366120.

Zfp36l1 establishes the high-affinity CD8 T-cell response by directly linking TCR affinity to cytokine sensing.

Petkau G, Mitchell T, Evans M, Matheson L, Salerno F, Turner M Eur J Immunol. 2023; 54(2):e2350700.

PMID: 38039407 PMC: 11146077. DOI: 10.1002/eji.202350700.

References

Gomez-Rodriguez J, Wohlfert E, Handon R, Meylan F, Wu J, Anderson S . Itk-mediated integration of T cell receptor and cytokine signaling regulates the balance between Th17 and regulatory T cells. J Exp Med. 2014; 211(3):529-43. PMC: 3949578. DOI: 10.1084/jem.20131459. View

Gallagher M, Conley J, Berg L . Peptide Antigen Concentration Modulates Digital NFAT1 Activation in Primary Mouse Naive CD8 T Cells as Measured by Flow Cytometry of Isolated Cell Nuclei. Immunohorizons. 2018; 2(7):208-215. PMC: 6135534. DOI: 10.4049/immunohorizons.1800032. View

Nayar R, Schutten E, Jangalwe S, Durost P, Kenney L, Conley J . IRF4 Regulates the Ratio of T-Bet to Eomesodermin in CD8+ T Cells Responding to Persistent LCMV Infection. PLoS One. 2015; 10(12):e0144826. PMC: 4699851. DOI: 10.1371/journal.pone.0144826. View

Rosette C, Werlen G, Daniels M, Holman P, Alam S, Travers P . The impact of duration versus extent of TCR occupancy on T cell activation: a revision of the kinetic proofreading model. Immunity. 2001; 15(1):59-70. DOI: 10.1016/s1074-7613(01)00173-x. View

Woronicz J, Calnan B, Ngo V, Winoto A . Requirement for the orphan steroid receptor Nur77 in apoptosis of T-cell hybridomas. Nature. 1994; 367(6460):277-81. DOI: 10.1038/367277a0. View

Nayar R, Schutten E, Bautista B, Daniels K, Prince A, Enos M . Graded levels of IRF4 regulate CD8+ T cell differentiation and expansion, but not attrition, in response to acute virus infection. J Immunol. 2014; 192(12):5881-93. PMC: 4080788. DOI: 10.4049/jimmunol.1303187. View

Yao S, Buzo B, Pham D, Jiang L, Taparowsky E, Kaplan M . Interferon regulatory factor 4 sustains CD8(+) T cell expansion and effector differentiation. Immunity. 2013; 39(5):833-45. PMC: 3855863. DOI: 10.1016/j.immuni.2013.10.007. View

Grumont R, Gerondakis S . Rel induces interferon regulatory factor 4 (IRF-4) expression in lymphocytes: modulation of interferon-regulated gene expression by rel/nuclear factor kappaB. J Exp Med. 2000; 191(8):1281-92. PMC: 2193138. DOI: 10.1084/jem.191.8.1281. View

Iwata A, Durai V, Tussiwand R, Briseno C, Wu X, Grajales-Reyes G . Quality of TCR signaling determined by differential affinities of enhancers for the composite BATF-IRF4 transcription factor complex. Nat Immunol. 2017; 18(5):563-572. PMC: 5401770. DOI: 10.1038/ni.3714. View

10.

Marangoni F, Murooka T, Manzo T, Kim E, Carrizosa E, Elpek N . The transcription factor NFAT exhibits signal memory during serial T cell interactions with antigen-presenting cells. Immunity. 2013; 38(2):237-49. PMC: 3582823. DOI: 10.1016/j.immuni.2012.09.012. View

11.

Hogan P, Chen L, Nardone J, Rao A . Transcriptional regulation by calcium, calcineurin, and NFAT. Genes Dev. 2003; 17(18):2205-32. DOI: 10.1101/gad.1102703. View

12.

Zhang N, Bevan M . CD8(+) T cells: foot soldiers of the immune system. Immunity. 2011; 35(2):161-8. PMC: 3303224. DOI: 10.1016/j.immuni.2011.07.010. View

13.

Donnadieu E, Lang V, Bismuth G, Ellmeier W, Acuto O, Michel F . Differential roles of Lck and Itk in T cell response to antigen recognition revealed by calcium imaging and electron microscopy. J Immunol. 2001; 166(9):5540-9. DOI: 10.4049/jimmunol.166.9.5540. View

14.

Dolmetsch R, Xu K, Lewis R . Calcium oscillations increase the efficiency and specificity of gene expression. Nature. 1998; 392(6679):933-6. DOI: 10.1038/31960. View

15.

Klein-Hessling S, Muhammad K, Klein M, Pusch T, Rudolf R, Floter J . NFATc1 controls the cytotoxicity of CD8 T cells. Nat Commun. 2017; 8(1):511. PMC: 5593830. DOI: 10.1038/s41467-017-00612-6. View

16.

Gomez-Rodriguez J, Meylan F, Handon R, Hayes E, Anderson S, Kirby M . Itk is required for Th9 differentiation via TCR-mediated induction of IL-2 and IRF4. Nat Commun. 2016; 7:10857. PMC: 4782063. DOI: 10.1038/ncomms10857. View

17.

Dura B, Dougan S, Barisa M, Hoehl M, Lo C, Ploegh H . Profiling lymphocyte interactions at the single-cell level by microfluidic cell pairing. Nat Commun. 2015; 6:5940. DOI: 10.1038/ncomms6940. View

18.

Ghosh S, Koralov S, Stevanovic I, Sundrud M, Sasaki Y, Rajewsky K . Hyperactivation of nuclear factor of activated T cells 1 (NFAT1) in T cells attenuates severity of murine autoimmune encephalomyelitis. Proc Natl Acad Sci U S A. 2010; 107(34):15169-74. PMC: 2930568. DOI: 10.1073/pnas.1009193107. View

19.

Hogquist K, Jameson S, Heath W, Howard J, Bevan M, Carbone F . T cell receptor antagonist peptides induce positive selection. Cell. 1994; 76(1):17-27. DOI: 10.1016/0092-8674(94)90169-4. View

20.

Miller A, Wilcox H, Lai Z, Berg L . Signaling through Itk promotes T helper 2 differentiation via negative regulation of T-bet. Immunity. 2004; 21(1):67-80. DOI: 10.1016/j.immuni.2004.06.009. View