Platelets fine-tune effector responses of naïve CD4⁺ T cells via platelet factor 4-regulated transforming growth factor β signaling.

Content Provider	Europe PMC
Author	Min, Yanan Hao, Long Liu, Xinguang Tan, Shuai Song, Hui Ni, Hao Sheng, Zi Jooss, Natalie Liu, Xuena Malmström, Rickard E. Sun, Yang Liu, Jianguo Tang, Hua Zhang, Hao Ma, Chunhong Peng, Jun Hou, Ming Li, Nailin
Abstract	Background and aimPlatelets are an able regulator of CD4+ T cell immunity. Herein, the mechanisms underlying platelet-regulated effector responses of naïve CD4+ T (Tn) cells were investigated.MethodsPlatelet–Tn cell co-cultures of human cells, genetically modified murine models, and high-throughput bioinformatic analyses were combined to elucidate molecular mechanisms of platelet-dependent regulation.ResultsPlatelets exerted sophisticated regulation on effector responses of type 1, 2, and 17 T helper (Th1/Th2/Th17) and regulatory T (Treg) cells, in time-, concentration-, and organ-dependent manners and with close cooperation of transforming growth factor β (TGFβ) and platelet factor 4 (PF4). PF4 at low concentrations reinforced TGFβ signaling by heteromerizing with type III TGFβ receptor (TGFBRIII), and subsequently enhanced TGFBRII expression and TGFβ signaling. High-concentration PF4 had, however, opposite effects by directly binding to TGFBRII, blocking TGFβ–TGFBRII ligation, and thus inhibiting TGFβ signaling. Furthermore, platelet depletion markedly hampered Treg and Th17 responses in the spleen but not in the lymph nodes, blockade of platelet–Tn cell contact diminished platelet effects, while spleen injection of PF4-immobilized microparticles in PF4-deficient mice mimicked platelet effects, suggesting the importance of direct platelet–Tn contact and platelet-bound PF4 for the optimal regulatory effects by platelets.ConclusionPlatelets exert context-dependent regulations on effector responses of Tn cells via PF4-TGFβ duet, suggesting new possibilities of platelet-targeted interventions of T cell immunity.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00018-022-04279-1.
ISSN	1420682X
Journal	Cellular and Molecular Life Sciences
Volume Number	79
PubMed Central reference number	PMC9016031
Issue Number	5
PubMed reference number	35437611
e-ISSN	14209071
DOI	10.1007/s00018-022-04279-1
Language	English
Publisher	Springer International Publishing
Publisher Date	2022-04-18
Publisher Place	Gewerbestrasse 11, Cham, Ch 6330, Switzerland
Access Restriction	Open
Rights License	Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. © The Author(s) 2022
Subject Keyword	Platelets Naïve CD4+ T cells Effector cell responses Platelet factor 4 Transforming growth factor β Type II TGFβ receptor Type III TGFβ receptor Platelet–T cell interactions
Content Type	Text
Resource Type	Article
Subject	Cell Biology Molecular Biology Molecular Medicine Pharmacology Cellular and Molecular Neuroscience