Abstract
Transforming growth factor-[beta] is an essential moderator of malaria- induced inflammation in mice. In this study, we show that the virulence of malaria infections is dependent upon the cellular source of TGF-[beta] and the timing of its production. C57BL/6 mice infected with a nonlethal (Py17X) strain of Plasmodium yoelii produce TGF-[beta] from 5 days postinfection; this correlates with resolution of parasitemia, down-regulation of TNF-[alpha], and full recovery. In contrast, infection with the lethal strain Py17XL induces high levels of circulating TGF-[beta] within 24 h; this is associated with delayed and blunted IFN-[gamma] and TNF-[alpha] responses, failure to clear parasites, and 100% mortality. Neutralization of early TGF-[beta] in Py17XL infection leads to a compensatory increase in IL-10 production, while simultaneous neutralization of TGF-[beta] and IL-10R signaling leads to up-regulation of TNF- [alpha] and IFN-[gamma], prolonged survival in all, and ultimate resolution of infection in 40% of Py17XL-infected animals. TGF-[beta] production can be induced in an Ag-specific manner from splenocytes of infected mice, and by cross-linking surface CTLA-4. CD25 super(+) and CD8 super(+) cells are the primary source of TGF-[beta] following Py17X stimulation of splenocytes, whereas Py17XL induces significant production of TGF-[beta] from adherent cells. In mice immunized against Py17XL, the early TGF-[beta] response is inhibited and is accompanied by significant up-regulation of IFN-[gamma] and TNF-[alpha] and rapid resolution of challenge infections.