A subset of neutrophils in human systemic inflammation inhibits T cell responses through Mac-1
Janesh Pillay, Vera M. Kamp, Els van Hoffen, Tjaakje Visser, Tamar Tak, Jan-Willem Lammers, Laurien H. Ulfman, Luke P. Leenen, Peter Pickkers, Leo Koenderman
Janesh Pillay, Vera M. Kamp, Els van Hoffen, Tjaakje Visser, Tamar Tak, Jan-Willem Lammers, Laurien H. Ulfman, Luke P. Leenen, Peter Pickkers, Leo Koenderman
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Research Article Immunology

A subset of neutrophils in human systemic inflammation inhibits T cell responses through Mac-1

Abstract

Suppression of immune responses is necessary to limit damage to host tissue during inflammation, but it can be detrimental in specific immune responses, such as sepsis and antitumor immunity. Recently, immature myeloid cells have been implicated in the suppression of immune responses in mouse models of cancer, infectious disease, bone marrow transplantation, and autoimmune disease. Here, we report the identification of a subset of mature human neutrophils (CD11cbright/CD62Ldim/CD11bbright/CD16bright) as what we believe to be a unique circulating population of myeloid cells, capable of suppressing human T cell proliferation. These cells were observed in humans in vivo during acute systemic inflammation induced by endotoxin challenge or by severe injury. Local release of hydrogen peroxide from the neutrophils into the immunological synapse between the neutrophils and T cells mediated the suppression of T cell proliferation and required neutrophil expression of the integrin Mac-1 (αMβ2). Our data demonstrate that suppression of T cell function can be accomplished by a subset of human neutrophils that can be systemically induced in response to acute inflammation. Identification of the pivotal role of neutrophil Mac-1 and ROS in this process provides a potential target for modulating immune responses in humans.

Authors

Janesh Pillay, Vera M. Kamp, Els van Hoffen, Tjaakje Visser, Tamar Tak, Jan-Willem Lammers, Laurien H. Ulfman, Luke P. Leenen, Peter Pickkers, Leo Koenderman

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Figure 2

Neutrophil phenotype after LPS administration (A) Neutrophils were stained for CD16 and CD62L to discriminate between the subsets.

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Neutrophil phenotype after LPS administration (A) Neutrophils were stain...
Additionally, they were stained with CD11b, CD11c, CD54, and CD88. Mean fluorescence intensity is depicted. Red lines depict CD16bright/CD62Ldim; gray lines depict CD16bright/CD62Lbright; green lines depict CD16dim/CD62Lbright. Graphs are representative of 5 experiments. (B) Neutrophil survival after 24 hours. Neutrophils subsets were FACS sorted, and cells were incubated for 24 hours at 37°C, 5% CO2; after incubation, they were stained with annexin V PE for 15 minutes and measured by flow cytometry. Data are expressed as the percentage of annexin V–negative, living cells (mean ± SEM; n = 5). (C) Relative increase in H2O2 in unsorted neutrophils measured by flow cytometry with DHR. Neutrophil subsets are visualized with CD16 and CD62L staining. Cells were stimulated with fMLF (10–6 M) and PAF (10–6 M) for 15 minutes. Neutrophils from healthy controls were used as a control. Graph shows relative increase in H2O2 release (mean ± SEM; n = 7). **P < 0.005; ***P < 0.001.