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Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
Published on: January 22, 2019
NKG2D-independent suppression of T cell proliferation by H60 and MICA
Anja K Kriegeskorte1, Friedemann E Gebhardt, Simona Porcellini
1Institute for Medical Microbiology, Immunology, and Hygiene, Technical University Munich, 81675 Munich, Germany.
Abstract:
The activating receptor NKG2D recognizes a wide range of different ligands, some of which are primarily expressed in "stressed" tissues or on tumor cells. Until now, similar stimulatory effects on natural killer and CD8+ T cells have been described for all NKG2D ligands, and the NKG2D receptor/ligand system has therefore been interpreted as a sensor system involved in tumor immune surveillance and activation of immune responses. We show here that the NKG2D ligands H60 and MIC class 1 chain-related protein A (MICA) can also mediate strong suppressive effects on T cell proliferation. Responsiveness to H60- and MICA-mediated suppression requires IL-10 and involves a receptor other than NKG2D. These findings might provide explanations for the observation that strong in vivo NKG2D ligand expression, such as that on tumor cells, sometimes fails to support effective immune responses and links this observation to a distinct subgroup of NKG2D ligands.
Insights
Certain NKG2D ligands, H60 and MICA, can suppress T cell proliferation. This suppression requires IL-10 and a receptor distinct from NKG2D, offering insights into immune responses against tumors.
Area of Science:
- Immunology
- Molecular Biology
- Cancer Research
Background:
- The NKG2D receptor-ligand system is crucial for immune surveillance, typically activating natural killer (NK) and CD8+ T cells against stressed or tumor cells.
- Previously, all known NKG2D ligands were thought to induce stimulatory effects, positioning NKG2D as a key sensor for immune activation.
Purpose of the Study:
- To investigate the functional dichotomy of NKG2D ligands, specifically examining if they can also mediate suppressive immune effects.
- To elucidate the mechanisms underlying potential suppressive functions of NKG2D ligands, including the involvement of specific cytokines and receptors.
Main Methods:
- Utilized cell-based assays to assess the impact of H60 and MICA on T cell proliferation.
- Investigated the role of interleukin-10 (IL-10) and alternative receptors in mediating the observed suppressive effects.
Main Results:
- Demonstrated that NKG2D ligands H60 and MICA can induce significant suppression of T cell proliferation, contrasting with previously understood stimulatory roles.
- Established that IL-10 is essential for H60- and MICA-mediated T cell suppression.
- Identified that the suppressive pathway involves a receptor distinct from NKG2D.
Conclusions:
- The NKG2D system exhibits a dual function, with certain ligands (H60, MICA) capable of suppressing T cell responses, not just activating them.
- Findings suggest a novel mechanism for immune evasion in cancer, explaining why high NKG2D ligand expression on tumors may not always lead to effective anti-tumor immunity.
- Highlights a distinct subgroup of NKG2D ligands that mediate immune suppression, mediated by IL-10 and a non-NKG2D receptor.
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