The Tec Kinase Itk Integrates Naïve T Cell Migration and Homeostasis.

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