Dataset Information

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

ABSTRACT:

Background and aim

Platelets 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.

Methods

Platelet-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.

Results

Platelets 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.

Conclusion

Platelets 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.

SUBMITTER: Min Y

PROVIDER: S-EPMC9016031 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Publications

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

Min Yanan Y Hao Long L Liu Xinguang X Tan Shuai S Song Hui H Ni Hao H Sheng Zi Z Jooss Natalie N Liu Xuena X Malmström Rickard E RE Sun Yang Y Liu Jianguo J Tang Hua H Zhang Hao H Ma Chunhong C Peng Jun J Hou Ming M Li Nailin N

Cellular and molecular life sciences : CMLS 20220418 5

<h4>Background and aim</h4>Platelets are an able regulator of CD4<sup>+</sup> T cell immunity. Herein, the mechanisms underlying platelet-regulated effector responses of naïve CD4<sup>+</sup> T (Tn) cells were investigated.<h4>Methods</h4>Platelet-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.<h4>Results</h4>Platelets exerted sophisticated regulati ...[more]

PMID: 35437611

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Project description:Transforming growth factor-β1 (TGFβ1) is the key profibrotic cytokine in idiopathic pulmonary fibrosis (IPF), but the primary source of this cytokine in this disease is unknown. Platelets have abundant stores of TGFβ1, although the role of these cells in IPF is ill-defined. In this study, we investigated whether platelets, and specifically platelet-derived TGFβ1, mediate IPF disease progression. Patients with IPF and non-IPF patients were recruited to determine platelet reactivity, and separate cohorts of patients with IPF were followed for mortality. To study whether platelet-derived TGFβ1 modulates pulmonary fibrosis (PF), mice with a targeted deletion of TGFβ1 in megakaryocytes and platelets (TGFβ1fl/fl.PF4-Cre) were used in the well-characterized bleomycin-induced pulmonary fibrosis (PF) animal model. In a discovery cohort, we found significantly higher mortality in patients with IPF who had elevated platelet counts within the normal range. However, our validation cohort did not confirm this observation, despite significantly increased platelets, neutrophils, active TGFβ1, and CCL5, a chemokine produced by inflammatory cells, in the blood, lung, and bronchoalveolar lavage (BAL) of patients with IPF. In vivo, we showed that despite platelets being readily detected within the lungs of bleomycin-treated mice, neither the degree of pulmonary inflammation nor fibrosis was significantly different between TGFβ1fl/fl.PF4-Cre and control mice. Our results demonstrate for the first time that platelet-derived TGFβ1 does not significantly mediate inflammation or fibrosis in a PF animal model. Furthermore, our human studies revealed blood platelet counts do not consistently predict mortality in IPF but other platelet-derived mediators, such as C-C chemokine ligand 5 (CCL5), may promote neutrophil recruitment and human IPF.NEW & NOTEWORTHY Platelets are a rich source of profibrotic TGFβ; however, the role of platelets in idiopathic pulmonary fibrosis (IPF) is unclear. We identified that patients with IPF have significantly more platelets, neutrophils, and active TGFβ in their airways than control patients. Using an animal model of IPF, we demonstrated that platelet-derived TGFβ does not significantly drive lung fibrosis or inflammation. Our findings offer a better understanding of platelets in both human and animal studies of IPF.

Dataset Information

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

Background and aim

Methods

Results

Conclusion

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

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

Background and aim

Methods

Results

Conclusion

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

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