Activation of Human T Cells by Major Histocompatability Complex Class II Expressing Neutrophils: Proliferation in the Presence of Superantigen, But Not Tetanus Toxoid

Abstract

The primary function of polymorphonuclear neutrophils (PMN) in the immune response appears to be acute phagocytic clearance of foreign pathogens and release of inflammatory mediators. Consistent with their assumed lack of major histocompatibility complex (MHC) class II expression, PMN have not been considered to play a role in antigen presentation and T-cell activation. However, recent reports have shown that human PMN can express MHC class II molecules both in vitro and in vivo after stimulation with either granulocyte-macrophage colony-stimulating factor (GM-CSF ) or interferon-γ (IFN-γ). Thus, under appropriate conditions, PMN could play a significant role in immune regulation, including T-cell activation. In this report, we demonstrate that human class II–expressing PMN can serve as accessory cells in superantigen (SAg)-mediated T-cell activation. This accessory activity for SAg presentation was present only after induction of MHC class II expression, and was especially pronounced following culture of PMN with GM-CSF plus IFN-γ, which acted synergistically to induce MHC class II molecules on PMN. Moreover, the level of MHC class II expression and the magnitude of SAg-induced T-cell responses were found to be highly correlated and distinctly donor dependent, with PMN from some donors repeatedly showing fivefold higher responses than PMN from other donors. On the other hand, culture of PMN with GM-CSF plus IFN-γ under conditions that resulted in optimal MHC class II expression did not enable them to function as antigen-presenting cells for either intact tetanus toxoid (TT) or for a TT peptide. These results delineate a new pathway for T-cell activation by SAg that may play an important role in the severity of SAg-induced inflammatory responses. They also identify a donor-specific polymorphism for induction of PMN MHC class II expression which may be of significance for therapies involving GM-CSF and IFN-γ.

Donor dependent, interferon-γinduced HLA-DR expression on human neutrophilsin vivo

“…However, the donor dependent IFN-γ mediated HLA-DR regulation in isolated neutrophils from healthy donors in vitro refutes this possibility. We even suggest that discrepant results reported on the in vitro regulation of MHC class II molecules via IFN-γ in studies with small numbers of healthy donors originate from the mechanisms described herein [12,19,20,27,28]. Different expression levels of HLA-DR on neutrophils during rhIFN-γ treatment could be explained by donor dependent pharmacokinetics of IFN-γ or by diverse induction of secondary mediators such as GM-CSF and IL-3, both known to regulate MHC class II molecules on these cells [12,13,17].…”

“…Due to the abundance of neutrophils in various inflammatory reactions the expression of HLA-DR on these cells could be essential in diseases, in which superantigens may contribute to pathogenesis such as rheumatic fever or inflammatory bowel disease [21]. Donor dependent variations in inducible HLA-DR expression on neutrophils may influence the course of these diseases as levels of neutrophil MHC class II expression and the magnitude of T cell responses are correlated functions [19].…”

Polymorphonuclear neutrophils as accessory cells for T‐cell activation: major histocompatibility complex class II restricted antigen‐dependent induction of T‐cell proliferation

“…While the data on MHC class II expression and presentation of SEE by PMN are in agreement with previous ®ndings, 17 . there is discrepancy with respect to presentation of peptide antigens.…”

Interferon‐γ activation of polymorphonuclear neutrophil function

“…18,19 These expressed MHC II molecules have even been shown to be at least partly functional, as the PMNs have been demonstrated to act as required accessory cells during T-cell activation with staphylococcal enterotoxin, a superantigen that does not require intracellular processing prior to presentation. 17 MHC II-expressing PMNs have also been shown to produce interleukin (IL)-8 when stimulated with this same superantigen. 20 The ability to fully process and present more fully processed antigens, such as tetanus toxoid, remains controversial.…”

“…In vitro experiments with PMNs may be casting doubt on this assumption, as a number of investigators have now reported that PMNs express MHC II on the cell surface when stimulated with IFN-c or other pro-inflammatory stimuli, such as GM-CSF. [16][17][18] CD80 and CD86, costimulatory molecules required for T-cell activation, have also been shown to be up-regulated under the same conditions as induce MHC II expression. 18,19 These expressed MHC II molecules have even been shown to be at least partly functional, as the PMNs have been demonstrated to act as required accessory cells during T-cell activation with staphylococcal enterotoxin, a superantigen that does not require intracellular processing prior to presentation.…”