Intraperitoneal Echinococcus multilocularis infection in C57BL/6 mice affects CD40 and B7 costimulator expression on peritoneal macrophages and impairs peritoneal T cell activation

Abstract

One of the most important immunopathological consequence of intraperitoneal alveolar echinococcosis (AE) in the mouse is suppression of T cell-mediated immune responses. We investigated whether and how intraperitoneal macrophages (MØs) are, respectively, implicated as antigen-presenting cells (APCs). In a first step we showed that peritoneal MØs from infected mice (AE-MØs) exhibited a reduced ability to present a conventional antigen (chicken ovalbumin, C-Ova) to specific responder lymph node T cells. In a subsequent step, AE-MØs as well as naïve MØs (positive control) proved their ability to uptake and process C-Ova fluorescein isthiocyanate (FITC). Furthermore, in comparison with naïve MØs, the surface expression of Ia molecules was up-regulated on AE-MØs at the early stage of infection, suggesting that AE-MØs provide the first signal via the antigen-Ia complex. To study the accessory activity of MØs, AE-MØs obtained at the early and late stages of infection were found to decrease Con A-induced proliferation of peritoneal naïve T cells as well as of AE-sensitized peritoneal T cells, in contrast to stimulation with naïve MØs. The status of accessory molecules was assessed by analysing the expression level of costimulatory molecules on AE-MØs, with naïve MØs as controls. It was found that B7-1 (CD80) and B7-2 (CD86) expression remained unchanged, whereas CD40 was down-regulated and CD54 (= ICAM-1) was slightly up-regulated. In a leucocyte reaction of AE-MØs with naïve or AE-T cells, both types of T cells increased their proliferative response when CD28 - the ligand of B7 receptors - was exposed to anti-CD28 in cultures. Conversely to naïve MØs, pulsing of AE-MØs with agonistic anti-CD40 did not even partially restore their costimulatory activity and failed to increase naïve or AE-T cell proliferation. Neutralizing anti-B7-1, in combination with anti-B7-2, reduced naïve and AE-T cell proliferation, whereas anti-CD40 treatment of naïve MØs increased their proliferative response to Con A. These results point at the key role of B7 receptors as accessory molecules and the necessity of the integrity of CD40-expression by naïve MØs to improve their accessory activity. Taken together, the obstructed presenting-activity of AE-MØs appeared to trigger an unresponsiveness of T cells, contributing to the suppression of their clonal expansion during the chronic phase of AE-infection.

In vitroinduction of lymph node cell proliferation by mouse bone marrow dendritic cells following stimulation with differentEchinococcus multilocularisantigens

“…DCs pulsed with the crude VF-antigen failed in this respect. Previous studies (Mejri & Gottstein, 2006) had already demonstrated a reduced presenting activity of E. multilocularisinfected host MØs, which appeared to trigger an unresponsiveness of T cells, leading to the suppression of their clonal expansion during the chronic phase of AE infection. Similar mechanisms may now also hold true for DCs.…”

Mechanisms of Immunity in Hydatid Disease: Implications for Vaccine Development

“…However, CD11 ϩ CD123 Ϫ myeloid DC pulsed with E. multilocularis Ags were able to induce autologous CD8 ϩ T cell proliferation (39), suggesting that the myeloid DC pathway is involved in CD8 ϩ T cell proliferation. Macrophages from mice infected with E. multilocularis can act as APC to process and present conventional Ags such as chicken OVA (59). CD8 ϩ T cells increase markedly during the course of E. multilocularis infection due to significant stimulation of a Th1-type cytokine IFN-␥ response and effector macrophage function (60).…”

Current trends in tissue-affecting helminths

“…FACS analysis of peritoneal cells revealed a decrease in the percentage of CD4 + and CD8 + T cells in AE-infected mice. Taken together, the obstructed presenting-activity of AE-MØ appeared to trigger an unresponsiveness of T cells leading to the suppression of their clonal expansion during the chronic phase of AE infection (Mejri & Gottstein, 2006).…”

“…Furthermore, Em492 (Walker et al, 2004) as a purified parasite metabolite suppresses ConA and antigen-stimulated splenocyte proliferation. Infected mouse macrophages (AE-MØ) as APCs exhibited a reduced ability to present a conventional antigen (chicken ovalbumin, C-Ova) to specific responder lymph node T cells when compared to normal MØ (Mejri & Gottstein, 2006). As AE-MØ fully maintained their capacity to appropriately process antigens, a failure in T cell receptor occupancy by antigen-Ia complex or/and altered co-stimulatory signals can be excluded.…”