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

Abstract

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

Keywords: CCL21/CCR7 axis; T cell trafficking; Tec kinase; chemokine; intravital 2-photon microscopy; signal transduction.