The Tec Kinase Itk Integrates Naïve T Cell Migration and In Vivo Homeostasis
Naïve T cells (TN) constitutively recirculate through secondary lymphatic organs (SLOs), where they scan dendritic cells (DCs) for cognate peptide-loaded major histocompatibility complexes (pMHC). Continuous trafficking between SLOs not only enables rapid clonal selection but also ensures TN homeost...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-09-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.716405/full |
| _version_ | 1819110202134233088 |
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| author | Flavian Thelen Stefanie Wissmann Nora Ruef Jens V. Stein |
| author_facet | Flavian Thelen Stefanie Wissmann Nora Ruef Jens V. Stein |
| author_sort | Flavian Thelen |
| collection | DOAJ |
| description | Naïve T cells (TN) constitutively recirculate through secondary lymphatic organs (SLOs), where they scan dendritic cells (DCs) for cognate peptide-loaded major histocompatibility complexes (pMHC). Continuous trafficking between SLOs not only enables rapid clonal selection but also ensures TN homeostasis by providing access to prosurvival signals from TCR, IL-7R, and the chemokine receptor CCR7. Inside the lymphoid tissue, CCR7-mediated TN motility is mainly driven by the Rac activator DOCK2, with a separate contribution by a phosphoinositide-3-kinase γ (PI3Kγ)-dependent pathway. Tec tyrosine kinases and the Rac activator Tiam1 constitute prominent downstream effectors of PI3K signaling. Yet, the precise role of Tec kinase versus Tiam1 signaling during CCR7-mediated TN migration and homeostasis remains incompletely understood. Here, we examined the function of the Tec family member interleukin-2-inducible T-cell kinase (Itk) and Tiam1 during TN migration in vitro and in vivo using intravital microscopy. Itk deficiency caused a mild decrease in CCR7-triggered TN migration, mirroring observations made with PI3Kγ;-/- T cells, while lack of Tiam1 did not affect TN motility. In silico modeling suggested that reduced migration in the absence of Itk does not result in a substantial decrease in the frequency of TN encounters with DCs within the lymphoid tissue. In contrast, Itk was important to maintain in vivo homeostasis of CD4+ TN, also in MHCII-deficient hosts. Taken together, our data suggest that Itk contributes to TN migration and survival by integrating chemokine receptor and TCR signaling pathways. |
| first_indexed | 2024-12-22T03:37:58Z |
| format | Article |
| id | doaj.art-dae30e21212b4a0c8a6ea7ff4f9ef814 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-22T03:37:58Z |
| publishDate | 2021-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-dae30e21212b4a0c8a6ea7ff4f9ef8142022-12-21T18:40:19ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-09-011210.3389/fimmu.2021.716405716405The Tec Kinase Itk Integrates Naïve T Cell Migration and In Vivo HomeostasisFlavian Thelen0Stefanie Wissmann1Nora Ruef2Jens V. Stein3Department of Medical Oncology and Hematology, University of Zürich and University Hospital Zürich, Zürich, SwitzerlandDepartment of Oncology, Microbiology and Immunology, University of Fribourg, Fribourg, SwitzerlandDepartment of Oncology, Microbiology and Immunology, University of Fribourg, Fribourg, SwitzerlandDepartment of Oncology, Microbiology and Immunology, University of Fribourg, Fribourg, SwitzerlandNaïve T cells (TN) constitutively recirculate through secondary lymphatic organs (SLOs), where they scan dendritic cells (DCs) for cognate peptide-loaded major histocompatibility complexes (pMHC). Continuous trafficking between SLOs not only enables rapid clonal selection but also ensures TN homeostasis by providing access to prosurvival signals from TCR, IL-7R, and the chemokine receptor CCR7. Inside the lymphoid tissue, CCR7-mediated TN motility is mainly driven by the Rac activator DOCK2, with a separate contribution by a phosphoinositide-3-kinase γ (PI3Kγ)-dependent pathway. Tec tyrosine kinases and the Rac activator Tiam1 constitute prominent downstream effectors of PI3K signaling. Yet, the precise role of Tec kinase versus Tiam1 signaling during CCR7-mediated TN migration and homeostasis remains incompletely understood. Here, we examined the function of the Tec family member interleukin-2-inducible T-cell kinase (Itk) and Tiam1 during TN migration in vitro and in vivo using intravital microscopy. Itk deficiency caused a mild decrease in CCR7-triggered TN migration, mirroring observations made with PI3Kγ;-/- T cells, while lack of Tiam1 did not affect TN motility. In silico modeling suggested that reduced migration in the absence of Itk does not result in a substantial decrease in the frequency of TN encounters with DCs within the lymphoid tissue. In contrast, Itk was important to maintain in vivo homeostasis of CD4+ TN, also in MHCII-deficient hosts. Taken together, our data suggest that Itk contributes to TN migration and survival by integrating chemokine receptor and TCR signaling pathways.https://www.frontiersin.org/articles/10.3389/fimmu.2021.716405/fullT cell traffickingchemokinesignal transductionTec kinaseCCL21/CCR7 axisintravital 2-photon microscopy |
| spellingShingle | Flavian Thelen Stefanie Wissmann Nora Ruef Jens V. Stein The Tec Kinase Itk Integrates Naïve T Cell Migration and In Vivo Homeostasis Frontiers in Immunology T cell trafficking chemokine signal transduction Tec kinase CCL21/CCR7 axis intravital 2-photon microscopy |
| title | The Tec Kinase Itk Integrates Naïve T Cell Migration and In Vivo Homeostasis |
| title_full | The Tec Kinase Itk Integrates Naïve T Cell Migration and In Vivo Homeostasis |
| title_fullStr | The Tec Kinase Itk Integrates Naïve T Cell Migration and In Vivo Homeostasis |
| title_full_unstemmed | The Tec Kinase Itk Integrates Naïve T Cell Migration and In Vivo Homeostasis |
| title_short | The Tec Kinase Itk Integrates Naïve T Cell Migration and In Vivo Homeostasis |
| title_sort | tec kinase itk integrates naive t cell migration and in vivo homeostasis |
| topic | T cell trafficking chemokine signal transduction Tec kinase CCL21/CCR7 axis intravital 2-photon microscopy |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2021.716405/full |
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