Protein Tyrosine Phosphatase Non-Receptor Type 2 Function in Dendritic Cells Is Crucial to Maintain Tissue Tolerance.

Larissa Hering,Egle Katkeviciute,Juliana Komuczki,Michael Scharl,Dunja Mrdjen,Silvia Lang,Philipp Busenhart,Marianne R Spalinger,Gerhard Rogler,Marcin Wawrzyniak,Kirstin Atrott,Marlene Schwarzfischer,Burkhard Becher,Claudia Gottier

doi:10.3389/fimmu.2020.01856

Abstract

Protein tyrosine phosphatase non-receptor type 2 (PTPN2) plays a pivotal role in immune homeostasis and has been associated with human autoimmune and chronic inflammatory diseases. Though PTPN2 is well-characterized in lymphocytes, little is known about its function in innate immune cells. Our findings demonstrate that dendritic cell (DC)-intrinsic PTPN2 might be the key to explain the central role for PTPN2 in the immune system to maintain immune tolerance. Partial genetic PTPN2 ablation in DCs resulted in spontaneous inflammation, particularly in skin, liver, lung and kidney 22 weeks post-birth. DC-specific PTPN2 controls steady-state immune cell composition and even incomplete PTPN2 deficiency in DCs resulted in enhanced organ infiltration of conventional type 2 DCs, accompanied by expansion of IFNγ-producing effector T-cells. Consequently, the phenotypic effects of DC-specific PTPN2 deficiency were abolished in T-cell deficient Rag knock-out mice. Our data add substantial knowledge about the molecular mechanisms to prevent inflammation and maintain tissue tolerance.

Highlights

Immune tolerance is indispensable to maintain tissue homeostasis and to avoid autoimmune responses
We investigated this hypothesis by generating mice lacking protein tyrosine phosphatase non-receptor type 2 (PTPN2) in dendritic cell (DC) (PTPN2fl/fl × CD11cCre mice)
DCs, but not other immune cells, displayed a 30% reduction in PTPN2 expression when compared to cells from PTPN2fl/fl mice (Figure S1), while in macrophages, PTPN2 expression was increased (Figure S1)

Summary

Introduction

Immune tolerance is indispensable to maintain tissue homeostasis and to avoid autoimmune responses. Dendritic cells (DCs) are key regulators of tolerance and controlled immune reactions. DCs sense danger signals (e.g., from invading pathogens) and convert them into activating signals for adaptive immune cells [1], holding a key position between innate and adaptive immunity. A deeper understanding of the key mechanisms that regulate DC activation and subsequent induction, promotion, and regulation of immune responses provides fundamental insights into human pathology of inflammatory diseases. First insights into mechanisms of this considerable range of PTPN2 in Dendritic Cells disease associations came from the observation that PTPN2 negatively regulates pro-inflammatory signaling cascades [6,7,8,9]. PTPN2-deficient (Ptpn2−/−) mice display severe immune defects with progressive systemic inflammation which is lethal within 5 weeks after birth demonstrating the important role of PTPN2 in immune regulation [10, 11]

Methods

Results

Conclusion