Apoptosis by Neglect of CD4+ Th Cells in Granulomas: A Novel Effector Mechanism Involved in the Control of Egg-Induced Immunopathology in Murine Schistosomiasis

Abstract

In infection with Schistosoma mansoni, parasite eggs precipitate an intrahepatic granulomatous and fibrosing inflammation that is mediated by CD4+ Th cells. Compared with CBA mice, C57BL/6 mice develop smaller granulomas composed of cells that exhibit reduced proliferative responses to schistosome egg Ags. In the present study, we investigated CD4+ T cell apoptosis as a possible mechanism that could account for this subdued response. We found throughout the course of several infection weeks a markedly higher proportion of apoptotic CD4+ T cells in granulomas from C57BL/6 mice than in those from CBA mice ex vivo; the apoptosis further increased upon cell cultivation in vitro. Activation-induced cell death or CD8+ T cells failed to account for the enhanced apoptosis as infected Fas-, Fas ligand,- and CD8-deficient mice exhibited similar apoptosis to that seen in wild-type counterparts. However, a strikingly lower IL-2 production by schistosome egg Ag-stimulated C57BL/6 granuloma and mesenteric lymph node cells suggested the possibility of apoptosis due to growth factor deprivation. Indeed, the CD4+ T cell apoptosis was significantly reversed by addition of rIL-2 in vitro, or by injection of rIL-2 in vivo, which also resulted in significant exacerbation of granulomatous inflammation. These findings indicate that apoptosis by neglect can represent a significant means of controlling CD4+ T cells that mediate the immunopathology in schistosomiasis.

Identifying phenotypes involved in susceptibility to Schistosoma mansoni infection in F1B6CBA mice

“…In this sense, we found an increase in the T-CD4 levels at initial stages of S. mansoni infection followed by a deep suppression of T-CD4+ expression in F1CBAB6 and their parental strains. Several studies have indicated that schistosomes are able to induce the death of CD4+ T cells through the binding of Fas-ligand (Rutitzky et al 2003). Interestingly, we found that C57/BL6 presented higher levels in monocytes population at nine weeks after infection than CBA/2J.…”

Th2 cell hyporesponsiveness during chronic murine schistosomiasis is cell intrinsic and linked to GRAIL expression

“…An important unresolved issue is the fate of the Th2 cell population as the infection progresses into the chronic phase. Several groups have reported increased Th cell apoptosis during infection (23)(24)(25), leading some to hypothesize that Th2 cell death accounts for the diminished proliferative and cytokine responses in chronic infection. Other groups have suggested that Th2 cells are present but rendered inactive either through illdefined cell-intrinsic mechanisms (26,27) or as a result of extrinsic factors, such as the presence of IL-10 (28-30) or altered Ag presentation (31).…”

CD4 T cells producing pro-inflammatory interleukin-17 mediate high pathology in schistosomiasis

“…Several independent lines of evidence have linked the high pathology to the persistence of a net pro-inflammatory state marked by the increase of Th1-type cytokines such as interferon (IFN)-γ and tumor necrosis factor (TNF)-α, the deficiency of anti-inflammatory Th2-type cytokines such as interleukin (IL)-4 and IL-10, or both. For example, schistosome egg antigen (SEA)-stimulated mesenteric lymph node cells from 7 week-infected high pathology CBA mice produce significant amounts of IFN-γ, whereas those from low pathology BL/ 6 mice do not (Rutitzky et al 2001(Rutitzky et al , 2003a(Rutitzky et al , 2005a. Moreover, mice with impaired costimulatory B7-CD28 (King et al 1996, Hernandez et al 1999 (Rutitzky et al 2003b) systems, or deficient in anti-inflammatory cytokines IL-4 (Brunet et al 1997) and IL-10 (Hoffmann et al 2000, Sadler et al 2003, or in B cells (Hernandez et al 1997) or in alternatively activated macrophages (Herbert et al 2004), display a pro-inflammatory cytokine dominance and are prone to pathology exacerbation.…”

“…IL-12 is a heterodimeric 70 kDa cytokine composed of two subunits of 40 and 35 kDa, termed IL-12p40 and IL-12p35 (Trinchieri 1998, 2003a. IL-12 is produced by activated innate immunocytes, such as dendritic cells (DC), and is recognized by lymphocytes expressing IL-12Rβ1 and IL-12Rβ2 receptors for the IL-12p40 and IL-12p35 subunits, respectively, thereby inducing IFN-γ and other pro-inflammatory mediator production (Trinchieri 1998(Trinchieri , 2003.…”