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Published on: September 28, 2018
Human profilin 1 is a negative regulator of CTL mediated cell-killing and migration
Rouven Schoppmeyer1, Renping Zhao1, He Cheng2,3,4
1Biophysics, Center for Integrative Physiology and Molecular Medicine, School of Medicine, Saarland University, Homburg, Germany.
Abstract:
The actin-binding protein profilin1 (PFN1) plays a central role in actin dynamics, which is essential for cytotoxic T lymphocyte (CTL) functions. The functional role of PFN1 in CTLs, however still remains elusive. Here, we identify PFN1 as the only member of the profilin family expressed in primary human CD8+ T cells. Using in vitro assays, we find that PFN1 is a negative regulator of CTL-mediated elimination of target cells. Furthermore, PFN1 is involved in activation-induced lytic granule (LG) release, CTL migration and modulation of actin structures at the immunological synapse (IS). During CTL migration, PFN1 modulates the velocity, protrusion formation patterns and protrusion sustainability. In contrast, PFN1 does not significantly affect migration persistence and the rates of protrusion emergence and retraction. Under in vitro conditions mimicking a tumor microenvironment, we show that PFN1 downregulation promotes CTL invasion into a 3D matrix, without affecting the viability of CTLs in a hydrogen peroxide-enriched microenvironment. Highlighting its potential relevance in cancer, we find that in pancreatic cancer patients, PFN1 expression is substantially decreased in peripheral CD8+ T cells. Taken together, we conclude that PFN1 is a negative regulator for CTL-mediated cytotoxicity and may have an impact on CTL functionality in a tumor-related context.
Insights
Profilin1 (PFN1) negatively regulates cytotoxic T lymphocyte (CTL) function, impacting their migration and killing ability. PFN1 downregulation may enhance CTL anti-tumor activity in specific cancer contexts.
Area of Science:
- Immunology
- Cell Biology
- Cancer Research
Background:
- Actin dynamics are crucial for cytotoxic T lymphocyte (CTL) functions.
- The role of actin-binding protein profilin1 (PFN1) in CTLs is not well understood.
- PFN1 is the sole profilin family member expressed in human CD8+ T cells.
Purpose of the Study:
- To elucidate the functional role of PFN1 in human CD8+ T cells.
- To investigate PFN1's impact on CTL-mediated cytotoxicity and migration.
- To assess PFN1's relevance in a tumor microenvironment and cancer patients.
Main Methods:
- In vitro assays to assess CTL-mediated target cell elimination.
- Analysis of PFN1's role in activation-induced lytic granule release and CTL migration.
- Examination of actin structures at the immunological synapse (IS).
- In vitro 3D matrix invasion assays under tumor microenvironment conditions.
- Analysis of PFN1 expression in peripheral CD8+ T cells from pancreatic cancer patients.
Main Results:
- PFN1 acts as a negative regulator of CTL-mediated target cell elimination.
- PFN1 influences CTL migration velocity, protrusion patterns, and sustainability, but not persistence or protrusion rates.
- PFN1 is involved in lytic granule release and actin remodeling at the IS.
- PFN1 downregulation enhances CTL invasion into 3D matrices, independent of hydrogen peroxide-induced viability changes.
- PFN1 expression is significantly decreased in CD8+ T cells of pancreatic cancer patients.
Conclusions:
- PFN1 negatively regulates CTL cytotoxicity and impacts CTL migration and actin dynamics.
- PFN1 modulation affects CTL invasion in simulated tumor microenvironments.
- Decreased PFN1 expression in pancreatic cancer patients suggests a potential role in anti-tumor immunity.
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