CD28 ligation increases macrophage suppression of T-cell proliferation

Abstract

When compared to spleen or lymph node cells, resident peritoneal cavity cells respond poorly to T cell activation in vitro. The greater proportional representation of macrophages in this cell source has been shown to actively suppress the T cell response. Peritoneal macrophages exhibit an immature phenotype (MHC Class IIlo, B7lo) that reduces their efficacy as antigen presenting cells. Furthermore, these cells readily express inducible nitric oxide synthase (iNOS), an enzyme that promotes T cell tolerance by catabolism of the limiting amino acid arginine. Here, we investigate the ability of exogenous T cell costimulation to recover the peritoneal T cell response. We show that CD28 ligation failed to recover the peritoneal T cell response and actually suppressed responses that had been recovered by inhibiting iNOS. As indicated by cytokine ELISpot and neutralizing mAb treatment, this “co-suppression” response was due to CD28 ligation increasing the number of IFNγ-secreting cells. Our results illustrate that cellular composition and cytokine milieu influence T cell costimulation biology.

Erythropoietin increases macrophage-mediated T cell suppression

“…1B). These results demonstrate the utility of this culture model for studying macrophage suppression of T cell activation [41–44]. …”

“…For each experiment 3–5 wells were established for each test group. As noted in our prior studies [42,44], media only controls routinely had < 1000 CPM and were excluded from figures.…”

“…Although these tumors often have antigen-specific T cells in situ , these cells are unresponsive. Such TMEs can be modeled in vitro via PerC cell culture wherein macrophage-dense conditions suppress T cell activation via catabolism of limiting amino acids, production of anti-inflammatory cytokines, and prostaglandin metabolism [41–44]. Data herein show that EPO increases T cell suppression in PerC cell culture by increasing macrophage catabolism of arginine.…”

Macrophage regulation of B cell proliferation

“…C57BL/6J PerC Mϕs temper TCR-triggered activation by inducing IFNγ-driven iNOS expression, which promotes proliferative arrest via arginine catabolism [11,12,14]. Inhibition of iNOS with 1-MA or neutralization of IFNγ abrogated PerC T cell suppression (Fig.…”

“…We have shown that peritoneal cavity (PerC) T cell proliferation is suppressed by the increased representation of macrophages present in this cell source [11]. T cell proliferation is regulated via catabolism of limiting amino acids, production of anti-inflammatory cytokines, and prostaglandin production [11–14]. PerC cell preparations include a significant fraction of B cells, notably the B1 subset distinctive for antibody responses to commensal microflora [15].…”