A subset of neutrophils in human systemic inflammation inhibits T cell responses through Mac-1
Janesh Pillay, … , Peter Pickkers, Leo Koenderman
Janesh Pillay, … , Peter Pickkers, Leo Koenderman
Published December 12, 2011
Citation Information: J Clin Invest. 2012;122(1):327-336. https://doi.org/10.1172/JCI57990.
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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 3

T cell proliferation after incubation with neutrophil subsets.

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T cell proliferation after incubation with neutrophil subsets. Blood was...
Blood was drawn 180 minutes after LPS administration, neutrophils were stained for CD16 and CD62L, and subsets were sorted. PBMCs were isolated from blood drawn before LPS administration and isolated by ficoll gradient separation. T cell proliferation was measured by [3H]thymidine incorporation. (A) PBMCs were stimulated with PHA (10 μg/ml) and incubated with different concentrations of the neutrophil subsets for 4 days. Data are depicted as the percentage inhibition of proliferation (mean ± SEM; n = 7). (B) PBMCs were stimulated with CD3 at 0.15 μg/m/CD28 at 1 μg/ml and incubated with different concentrations of the neutrophil subsets for 4 days. Data are presented as mean ± SEM; n = 7. (C) PBMCs from healthy volunteers who had received a tetanus booster vaccination less than 5 years ago were stimulated with tetanus toxoid, incubated with CD62Ldim or CD16dim neutrophils, and added in a 2:1 neutrophil-to-lymphocyte ratio for 4 days. Data are depicted as the percentage inhibition of proliferation (mean ± SEM; n = 10). (D) T cell apoptosis in neutrophil cocultures. Neutrophils were added in a 2:1 ratio in culture conditions described for the T cell proliferation cultures. At various time points, cells were stained with CD3 FITC and annexin V PE, and apoptosis was measured by gating the CD3-positive cells by flow cytometry. Data are depicted as the percentage of living cells (mean ± SEM; n = 4). *P < 0.05; ***P < 0.001.