CD80+Gr-1+ Myeloid Cells Inhibit Development of Antifungal Th1 Immunity in Mice with Candidiasis

Abstract

To find out whether polymorphonuclear neutrophils (PMN), abundantly recruited in disseminated Candida albicans infection, could directly affect the activation of Th cells we addressed the issues as to whether murine PMN, like their human counterparts, express costimulatory molecules and the functional consequence of this expression in terms of antifungal immune resistance. To this purpose, we assessed 1) the expression of CD80 (B7-1) and CD86 (B7-2) molecules on peripheral, splenic, and inflammatory murine Gr-1+ PMN; 2) its modulation upon interaction with C. albicans in vitro, in vivo, and in human PMN; 3) the effect of Candida exposure on the ability of murine PMN to affect CD4+ Th1 cell proliferation and cytokine production; and 4) the mechanism responsible for this effect. Murine PMN constitutively expressed CD80 molecules on both the surface and intracellularly; however, in both murine and human PMN, CD80 expression was differentially modulated upon interaction with Candida yeasts or hyphae in vitro as well as in infected mice. The expression of the CD86 molecule was neither constitutive nor inducible upon exposure to the fungus. In vitro, Gr-1+ PMN were found to inhibit the activation of IFN-γ-producing CD4+ T cells and to induce apoptosis through a CD80/CD28-dependent mechanism. A population of CD80+Gr-1+ myeloid cells was found to be expanded in conventional as well as in bone marrow-transplanted mice with disseminated candidiasis, but its depletion increased the IFN-γ-mediated antifungal resistance. These data indicate that alternatively activated PMN expressing CD80 may adversely affect Th1-dependent resistance in fungal infections.

A Major Role for Myeloid-Derived Suppressor Cells and a Minor Role for Regulatory T Cells in Immunosuppression during Staphylococcus aureus Infection

“…Immunosuppression of T cells during Trypanosoma cruzi (47) and Toxoplasma gondii (48) infection also was linked to MDSC. A similar immunosuppressive effect of MDSC was demonstrated during infections with helminths (49,50) and Candida albicans (51), and a very recent publication reported the contribution of MDSC to orthopedic biofilm infection caused by S. aureus (44). In our study, we provide evidence for an expansion of MDSC with immunosuppressive effect during the chronic phase of infection in a murine model of systemic S. aureus infection.…”

CD80 in Immune Suppression by Mouse Ovarian Carcinoma–Associated Gr-1+CD11b+ Myeloid Cells

“…Thus, it is possible that 1D8 ovarian carcinoma-derived factors could render Gr-1 + CD11b + cells of naïve mice immunosuppressive. CD80 expression has been described as a surface marker of MSCs expanded in mice with disseminated candidiasis, and its depletion increased IFNg-mediated antifungal resistance (20,41). This finding suggested a possible suppressive role for CD80 in the activity of MSCs.…”

“…However, reports differ in the outcome of CD80-dependent signaling in regulating T cell activity (42). Thus, we hypothesized that CD80 expression by the ovarian carcinoma-associated Gr-1 + CD11b + MSCs might contribute to the suppression of antigen-specific immunity and the induction of tumor immunotolerance (20,41). To address the role of CD80 in the suppressive effects of Gr-1 + CD11b + MSCs on antigen-specific T cell responses, we again used splenocytes from mice vaccinated with the potent heterologous antigen, HPV16 L1 VLPs.…”

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

“…Recently, however, a role for myeloid cells that mediate immune suppression has gained much attention (1). A heterogeneous group of cells, referred to as myeloid-derived suppressor cells (MDSCs), has been shown to directly suppress T cell functions in murine models of cancer, infectious diseases, bone marrow transplantation, and autoimmune diseases (2)(3)(4)(5). The immunesuppressive characteristics of these MDSCs are thought to limit the effectiveness of anticancer vaccines (6).…”