Platelet factor 4 limits Th17 differentiation and cardiac allograft rejection
Guanfang Shi, David J. Field, Kyung-ae Ko, Sara Ture, Kalyan Srivastava, Scott Levy, M. Anna Kowalska, Mortimer Poncz, Deborah J. Fowell, Craig N. Morrell
Guanfang Shi, David J. Field, Kyung-ae Ko, Sara Ture, Kalyan Srivastava, Scott Levy, M. Anna Kowalska, Mortimer Poncz, Deborah J. Fowell, Craig N. Morrell
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Research Article

Platelet factor 4 limits Th17 differentiation and cardiac allograft rejection

Abstract

Th cells are the major effector cells in transplant rejection and can be divided into Th1, Th2, Th17, and Treg subsets. Th differentiation is controlled by transcription factor expression, which is driven by positive and negative cytokine and chemokine stimuli at the time of T cell activation. Here we discovered that chemokine platelet factor 4 (PF4) is a negative regulator of Th17 differentiation. PF4-deficient and platelet-deficient mice had exaggerated immune responses to cardiac transplantation, including increased numbers of infiltrating Th17 cells and increased plasma IL-17. Although PF4 has been described as a platelet-specific molecule, we found that activated T cells also express PF4. Furthermore, bone marrow transplantation experiments revealed that T cell–derived PF4 contributes to a restriction in Th17 differentiation. Taken together, the results of this study demonstrate that PF4 is a key regulator of Th cell development that is necessary to limit Th17 differentiation. These data likely will impact our understanding of platelet-dependent regulation of T cell development, which is important in many diseases, in addition to transplantation.

Authors

Guanfang Shi, David J. Field, Kyung-ae Ko, Sara Ture, Kalyan Srivastava, Scott Levy, M. Anna Kowalska, Mortimer Poncz, Deborah J. Fowell, Craig N. Morrell

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Figure 6

Activated T cell–derived PF4 limits Th17 differentiation.

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Activated T cell–derived PF4 limits Th17 differentiation. (A) T cells we...
(A) T cells were isolated from Pf4-Cre+ Rosa26 flox-stop-flox mice and cultured in resting or activated conditions (anti-CD3 and anti-CD28, 1 μg/ml). EYFP-positive CD4+ and CD8+ T cells were quantified by flow cytometry (n = 4; mean ± SD. *P < 0.01 vs. Resting). (B) Stimulated T cells produce PF4. ELISA for PF4 in 4 day cell culture supernatants (n = 4; mean ± SD. *P < 0.01 vs. Control). (C) PF4 expression is induced in T cells in vivo. Mice were given cardiac transplants, and after 7 days CD4+ cells were isolated to measure Cxcl4 expression relative to control mice by qRT-PCR (n = 4; mean ± SD; *P < 0.01 vs. Control). (D) T cell PF4 can compensate partially for a lack of platelet PF4. Nude mice were given WT or Pf4–/– T cell–depleted bone marrow transplants, and reconstituted with either WT or Pf4–/– T cells. Mice were then given cardiac transplants, and plasma IL-17 was measured (n = 4; mean ± SD; *P < 0.05 vs. WT/WT).