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Regulatory T Cells Control PF4/Heparin Antibody Production in Mice. J Immunol 2019 10 01;203(7):1786-1792

Date

09/01/2019

Pubmed ID

31471526

Pubmed Central ID

PMC6944762

DOI

10.4049/jimmunol.1900196

Scopus ID

2-s2.0-85072761081   1 Citation

Abstract

Heparin-induced thrombocytopenia is a relatively common drug-induced immune disorder that can have life-threatening consequences for affected patients. Immune complexes consisting of heparin, platelet factor 4 (PF4), and PF4/heparin-reactive Abs are central to the pathogenesis of heparin-induced thrombocytopenia. Regulatory T (Treg) cells are a subpopulation of CD4 T cells that play a key role in regulating immune responses, but their role in controlling PF4/heparin-specific Ab production is unknown. In the studies described in this article, we found that Foxp3-deficient mice lacking functional Treg cells spontaneously produced PF4/heparin-specific Abs. Following transplantation with bone marrow cells from Foxp3-deficient but not wild-type mice, Rag1-deficient recipients also produced PF4/heparin-specific Abs spontaneously. Adoptively transferred Treg cells prevented spontaneous production of PF4/heparin-specific Abs in Foxp3-deficient mice and inhibited PF4/heparin complex-induced production of PF4/heparin-specific IgGs in wild-type mice. Treg cells suppress immune responses mainly through releasing anti-inflammatory cytokines, such as IL-10. IL-10-deficient mice spontaneously produced PF4/heparin-specific Abs. Moreover, bone marrow chimeric mice with CD4 T cell-specific deletion of IL-10 increased PF4/heparin-specific IgG production upon PF4/heparin complex challenge. Short-term IL-10 administration suppresses PF4/heparin-specific IgG production in wild-type mice. Taken together, these findings demonstrate that Treg cells play an important role in suppressing PF4/heparin-specific Ab production.

Author List

Zheng Y, Zhu W, Haribhai D, Williams CB, Aster RH, Wen R, Wang D

Authors

Richard H. Aster MD Professor in the Medicine department at Medical College of Wisconsin
Demin Wang PhD Assistant Professor in the Microbiology and Immunology department at Medical College of Wisconsin
Calvin B. Williams MD, PhD Chief, Professor in the Pediatrics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Antibody Formation
Forkhead Transcription Factors
Heparin
Immunoglobulin G
Interleukin-10
Mice
Mice, Knockout
Platelet Factor 4
T-Lymphocytes, Regulatory
jenkins-FCD Prod-469 c3fc8ab87196149f9b23743c01b947d47e7319e5