AUTHOR=Thelen Flavian , Wissmann Stefanie , Ruef Nora , Stein Jens V. 

TITLE=The Tec Kinase Itk Integrates Naïve T Cell Migration and In Vivo Homeostasis

JOURNAL=Frontiers in Immunology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.716405

DOI=10.3389/fimmu.2021.716405

ISSN=1664-3224

ABSTRACT=<p>Naïve T cells (T<sub>N</sub>) 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 T<sub>N</sub> homeostasis by providing access to prosurvival signals from TCR, IL-7R, and the chemokine receptor CCR7. Inside the lymphoid tissue, CCR7-mediated T<sub>N</sub> 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 T<sub>N</sub> 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 T<sub>N</sub> migration <italic>in vitro</italic> and <italic>in vivo</italic> using intravital microscopy. Itk deficiency caused a mild decrease in CCR7-triggered T<sub>N</sub> migration, mirroring observations made with PI3Kγ;<sup>-/-</sup> T cells, while lack of Tiam1 did not affect T<sub>N</sub> motility. <italic>In silico</italic> modeling suggested that reduced migration in the absence of Itk does not result in a substantial decrease in the frequency of T<sub>N</sub> encounters with DCs within the lymphoid tissue. In contrast, Itk was important to maintain <italic>in vivo</italic> homeostasis of CD4<sup>+</sup> T<sub>N</sub>, also in MHCII-deficient hosts. Taken together, our data suggest that Itk contributes to T<sub>N</sub> migration and survival by integrating chemokine receptor and TCR signaling pathways.</p>