Abstract
Lymphocytes are some of the most motile cells of vertebrates, constantly navigating through various organ systems. Their specific positioning in the body is delicately controlled by site-specific directional cues such as chemokines. While it has long been suspected that an intrinsic molecular pilot, akin to a ship’s pilot, guides lymphocyte navigation, the nature of this pilot is unknown. Here we show that the TIPE (TNF-α-induced protein 8-like) family of proteins pilot lymphocytes by steering them toward chemokines. TIPE proteins are carriers of lipid second messengers. They mediate chemokine-induced local generation of phosphoinositide second messengers, but inhibit global activation of the small GTPase Rac. TIPE-deficient T lymphocytes are completely pilot-less: they are unable to migrate toward chemokines despite their normal ability to move randomly. As a consequence, TIPE-deficient mice have a marked defect in positioning their T lymphocytes to various tissues, both at the steady-state and during inflammation. Thus, TIPE proteins pilot lymphocytes during migration and may be targeted for the treatment of lymphocyte-related disorders.
Highlights
Leukocyte migration in response to chemical attractants is essential for immune homeostasis, immunity, and inflammation1–4
We found that TIPE2 and TNFAIP8 deficiency completely abolished the directionality of T cells during chemokine-induced migration (Fig. 1)
Deficiency in either TIPE2 or TNFAIP8 alone did not significantly affect either directionality or velocity. These results indicate that TIPE2 and TNFAIP8 play redundant roles in controlling T cell directionality, and loss of one can be adequately compensated by the other
Summary
Leukocyte migration in response to chemical attractants is essential for immune homeostasis, immunity, and inflammation. The LEGI-BEN (local-excitation, global-inhibition - biased excitable network) model predicts that both enhancers and inhibitors of signal transduction are required for leukocyte polarization and chemotaxis. We report here that TIPE2 and TNFAIP8 play redundant roles in controlling lymphocyte migration Loss of both TIPE2 and TNFAIP8, but not either alone, is required to stop directional migration of lymphocytes. This Dual Molecular Redundancy (DMR) ensures that the direction of migration is maintained even when one TIPE protein fails (e.g., as a result of gene mutation or downregulation). It enhances the overall robustness of the system, as the DMR does in electric engineering
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