The role of ADAM17 in the T-cell response against bacterial pathogens.

Moritz Andreas Link,Valéa Schumacher,Karsten Lücke,Hans-Willi Mittrücker,Thomas Eden,Joanna Schmid,Stefan Rose-John,Stephen J Turner

doi:10.1371/journal.pone.0184320

Moritz Andreas Link, Valéa Schumacher + Show 6 more

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https://doi.org/10.1371/journal.pone.0184320

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Abstract

ADAM17 is a member of the A Disintegrin And Metalloproteinase family of proteases. It is ubiquitously expressed and causes the shedding of a broad spectrum of surface proteins such as adhesion molecules, cytokines and cytokine receptors. By controlled shedding of these proteins from leukocytes, ADAM17 is able to regulate immune responses. Several ADAM17 targets on T cells have been implicated in T-cell migration, differentiation and effector functions. However, the role of ADAM17 in T-cell responses is still unclear. To characterize the function of ADAM17 in T cells, we used Adam17fl/fl×CD4cre+ mice with a T-cell restricted inactivation of the Adam17 gene. Upon stimulation, ADAM17-deficient CD4+ and CD8+ T cells were impaired in shedding of CD62L, IL-6Rα, TNF-α, TNFRI and TNFRII. Surprisingly, we could not detect profound changes in the composition of major T-cell subsets in Adam17fl/fl×CD4cre+ mice. Following infection with Listeria monocytogenes, Adam17fl/fl×CD4cre+ mice mounted regular listeria-specific CD4+ TH1 and CD8+ T-cell responses and were able to control primary and secondary infections. In conclusion, our study indicates that ADAM17 is either not required in T cells under homoeostatic conditions and for control of listeria infection or can be effectively compensated by other mechanisms.

Highlights

Proteases of the ADAM (A Disintegrin And Metalloproteinase) family regulate various aspects of immune cell development and function
ADAM17 deletion was confirmed by FACS for loss of CD62L shedding from T cells after incubation of peripheral blood cells for 30 min with PMA and ionomycin
In the first set of experiments, we tested whether ADAM17-deficent T cells were able to shed verified ADAM17 substrates

Summary

Introduction

Proteases of the ADAM (A Disintegrin And Metalloproteinase) family regulate various aspects of immune cell development and function. ADAM proteases cause the release of cytokines and the ectodomain shedding of cell surface molecules including adhesion molecules and cytokine receptors [1, 2]. For ADAM17, more than 70 target proteins have been identified [2]. ADAM17 is responsible for the TNF-α release and for the paracrine and systemic activity of the cytokine [3, 4]. Inhibition of ADAM17 as well as global or myeloid cell-restricted deletion of ADAM17 in mice results in reduced systemic TNF-α levels following LPS treatment and protects mice from fatal endotoxemia [5, 6, 7]. Mice with defective iRhom (inactive Rhomboid protein 2), which facilitates trafficking of ADAM17 to the cell surface, are less susceptible to LPS endotoxemia [8, 9].

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