Abstract
The biological significance of membrane transfer (trogocytosis) between polymorphonuclear neutrophils (PMNs) and mononuclear cells (MNCs) remains unclear. We investigated the biological/immunological effects and molecular basis of trogocytosis among various immune cells in healthy individuals and patients with active systemic lupus erythematosus (SLE). By flow cytometry, we determined that molecules in the immunological synapse, including HLA class-I and-II, CD11b and LFA-1, along with CXCR1, are exchanged among autologous PMNs, CD4+ T cells, and U937 cells (monocytes) after cell-cell contact. Small interfering RNA knockdown of the integrin adhesion molecule CD11a in U937 unexpectedly enhanced the level of total membrane transfer from U937 to PMN cells. Functionally, phagocytosis and IL-8 production by PMNs were enhanced after co-culture with T cells. Total membrane transfer from CD4+ T to PMNs delayed PMN apoptosis by suppressing the extrinsic apoptotic molecules, BAX, MYC and caspase 8. This enhancement of activities of PMNs by T cells was found to be mediated via p38- and P44/42-Akt-MAP kinase pathways and inhibited by the actin-polymerization inhibitor, latrunculin B, the clathrin inhibitor, Pitstop-2, and human immunoglobulin G, but not by the caveolin inhibitor, methyl-β-cyclodextrin. In addition, membrane transfer from PMNs enhanced IL-2 production by recipient anti-CD3/anti-CD28 activated MNCs, and this was suppressed by inhibitors of mitogen-activated protein kinase (PD98059) and protein kinase C (Rottlerin). Of clinical significance, decreased total membrane transfer from PMNs to MNCs in patients with active SLE suppressed mononuclear IL-2 production. In conclusion, membrane transfer from MNCs to PMNs, mainly at the immunological synapse, transduces survival and activation signals to enhance PMN functions and is dependent on actin polymerization, clathrin activation, and Fcγ receptors, while membrane transfer from PMNs to MNCs depends on MAP kinase and PKC signaling. Defective membrane transfer from PMNs to MNCs in patients with active systemic lupus erythematous suppressed activated mononuclear IL-2 production.
Highlights
Polymorphonuclear neutrophils (PMNs) defend against bacterial invasion and interact via cytokines with other immune cells, including lymphocytes, antigen-presenting cells (APC), monocytes/macrophages and natural killer (NK) cells [1,2,3,4]
We investigated the proportions of normal PMNs, CD4+ T cells, and monocytes/macrophages engaged in trogocytosis, the functional alterations of cells after trogocytosis, and the molecular basis of these
Trogocytosis between PKH-67-labeled PMNs and PKH-26 -labeled CD4+ T cells was initially detected by flow cytometry (Fig 1A)
Summary
Polymorphonuclear neutrophils (PMNs) defend against bacterial invasion and interact via cytokines with other immune cells, including lymphocytes, antigen-presenting cells (APC), monocytes/macrophages and natural killer (NK) cells [1,2,3,4]. In PMN-depleted rats, delayedtype hypersensitivity and tumor inhibitory functions are suppressed, whereas humoral immune responses are enhanced [5,6,7,8]. Interferon (IFN)-γ, interleukin (IL)-3 and granulocyte-macrophage colony-stimulating factor can induce PMN to express major histocompatibility complex (MHC) class-II and the T cell co-stimulatory molecules CD80 and CD86, enabling them to act as APC, and enhance T cell proliferation [9,10,11]. PMNs modulate diverse immune functions of mononuclear cells (MNCs). The molecular basis of PMN-MNC interactions, other than those involving cytokines, remains unclear
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