We propose to demonstrate biologic and pathophysiologic roles for platelets via the chemokine platelet factor 4 (PF4) in T-helper cell homeostasis and chronic transplant immune responses. PF4 is best known for its role in the pathogenesis of heparin induced thrombocytopenia (HIT), but despite its high plasma concentration, biologic roles for PF4 are not well understood. Our new exciting data demonstrate that PF4 is needed to limit Th17 differentiation in both steady state and inflammatory conditions. We propose the hypothesis that platelets maintain T-helper balance in a PF4 dependent manner. This presents the novel concept of cross-talk between platelets and CD4+ T-cells and extends the role for platelets in immunity to an acquired immune role in the maintenance of T-helper balance. T-helper cells get their name from the fact that their cytokines influence many other cells such as increasing neutrophil and monocyte numbers and inflammatory profile and T-helper cells are necessary for B- cell antibody class switching. Therefore, platelet regulation of T-helper numbers and types implies a major role for platelets in immune homeostasis. T-helper cells are divided into Th1, Th2, Th17 and Tregs. Our data indicates that in the absence of PF4 there are greatly increased numbers of Th17 cells at steady state, and in a mouse model of vascularized cardiac transplant Th17 numbers increase greatly post-transplant. We have also discovered that PF4 expression and production is induced in T-cells post activation and T-cell PF4 also limits Th17 differentiation. As such we propose the following aims:
Aim 1 : To demonstrate that PF4 is a major mediator of T-helper differentiation.
Aim 2 : To demonstrate mechanisms for PF4 inhibition of Th17 differentiation. Results of our studies will impact many fields of inflammation related research, including transplant immune responses. Great progress has been made in reducing the incidence of acute transplant rejection, but less progress has been made in preventing chronic graft vasculopathy. Our results indicate a novel PF4 mediated pathway that regulates CD4+ T-cell responses to transplantation. These studies will also impact many other fields of inflammation and immune development by demonstrating a mechanism for platelet and T-cell cross-talk that directly affects immune development. We will use genetically modified thrombocytopenic and PF4 deficient mice in a chronic heart transplant model to pursue our novel and impactful studies.

Public Health Relevance

T-helper cells are critical regulators of immunity. We have identified platelet factor 4 (PF4) as a critical regulator of normal T-helper cell homeostasis and responses to transplantation. Our proposal will add novel insight into T-helper regulation in response to transplantation that will affect approaches to treating numerous other vascular and inflammatory diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL124018-04
Application #
9385749
Study Section
Hemostasis and Thrombosis Study Section (HT)
Program Officer
Sarkar, Rita
Project Start
2014-12-01
Project End
2019-11-30
Budget Start
2017-12-01
Budget End
2019-11-30
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Rochester
Department
Internal Medicine/Medicine
Type
School of Medicine & Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Cameron, Scott J; Mix, Doran S; Ture, Sara K et al. (2018) Hypoxia and Ischemia Promote a Maladaptive Platelet Phenotype. Arterioscler Thromb Vasc Biol 38:1594-1606
Schmidt, Rachel A; Morrell, Craig N; Ling, Frederick S et al. (2018) The platelet phenotype in patients with ST-segment elevation myocardial infarction is different from non-ST-segment elevation myocardial infarction. Transl Res 195:1-12
Yang, Moua; Kholmukhamedov, Andaleb; Schulte, Marie L et al. (2018) Platelet CD36 signaling through ERK5 promotes caspase-dependent procoagulant activity and fibrin deposition in vivo. Blood Adv 2:2848-2861
Field, David J; Aggrey-Amable, Angela A; Blick, Sara K et al. (2017) Platelet factor 4 increases bone marrow B cell development and differentiation. Immunol Res 65:1089-1094
Chapman, Lesley M; Ture, Sara K; Field, David J et al. (2017) miR-451 limits CD4+ T cell proliferative responses to infection in mice. Immunol Res 65:828-840
Yang, Moua; Cooley, Brian C; Li, Wei et al. (2017) Platelet CD36 promotes thrombosis by activating redox sensor ERK5 in hyperlipidemic conditions. Blood 129:2917-2927
Zhu, Qiuyu Martin; Ko, Kyung Ae; Ture, Sara et al. (2017) Novel Thrombotic Function of a Human SNP in STXBP5 Revealed by CRISPR/Cas9 Gene Editing in Mice. Arterioscler Thromb Vasc Biol 37:264-270
Xu, Suowen; Liu, Bin; Yin, Meimei et al. (2016) A novel TRPV4-specific agonist inhibits monocyte adhesion and atherosclerosis. Oncotarget 7:37622-37635
Modjeski, K L; Levy, S C; Ture, S K et al. (2016) Glutamate Receptor Interacting Protein 1 Regulates CD4(+) CTLA-4 Expression and Transplant Rejection. Am J Transplant 16:1383-93
Batchu, N; Hughson, Angie; Wadosky, Kristine M et al. (2016) Role of Axl in T-Lymphocyte Survival in Salt-Dependent Hypertension. Arterioscler Thromb Vasc Biol 36:1638-1646

Showing the most recent 10 out of 19 publications