Gamma delta T-cell function in pathogenesis of cerebral malaria in mice infected with Plasmodium berghei ANKA.

Mice depleted of gammadelta T cells by monoclonal antibody treatment and infected with Plasmodium berghei ANKA did not develop cerebral malaria (CM). In striking contrast, delta0/0 mice infected with P. berghei developed CM despite their gammadelta T-cell deficiency. gammadelta T cells appear to be essential for the pathogenesis of CM in mice having experienced normal ontogeny but not in mice genetically deprived of gammadelta T cells from the beginning of life.

Participation of lymphocyte subpopulations in the pathogenesis of experimental murine cerebral malaria.

We determined the requirement for selected lymphocyte subsets and cytokines in the pathogenesis of experimental murine cerebral malaria (CM) by using gene-targeted knockout and mAb-suppressed mice. Plasmodium berghei ANKA infection induced CM in A 0/0 mice, which lack expression of surface MHC class II glycoproteins and consequently express a severe and chronic reduction in numbers of CD4+ T cells. However, when A 0/0 mice, which are on a C57BL/6 x 129 genetic background, or immune-intact C57BL/6 controls treated with anti-CD4 mAb were infected, none developed CM. The latter finding confirms an earlier report that CD4+ T cells are required for CM to occur and additionally indicates that the reduced numbers of CD4+ T cells present in A 0/0 mice are sufficient for CM development. Neither the recently described CD4+, NK1.1+ T cell subset shown to be present in A 0/0 mice nor traditional NK cells seem to be required for the induction of CM because A 0/0 and C57BL/6 mice severely depleted of both NK1.1+ populations with mAb developed CM as readily as did normal Ig-treated controls. Deficiency of Th1-associated cytokines (IFN-gamma or IL-2) in mice by gene-targeted disruptions completely inhibited CM development, whereas the lack of Th2-associated cytokines (IL-4 or IL-10) did not prevent this disease. Our observation that B cell-deficient JHD and microMT mice developed CM provides evidence that neither B cells, their products, nor B cell Ag presentation are a requisite for CM pathology. We further observed that neither beta 2m 0/0 knockout mice, which lack CD8+ alpha beta T cells, nor C57BL/6 mice depleted of CD8+ T cells with anti-CD8 mAb treatment developed CM, leading us to conclude that CD8+ T cells are also crucial for the development of CM.

Plasmodium yoelii: splenectomy alters the antibody responses of infected mice.

The antibody response to Plasmodium yoelii is altered in splenectomized mice. Sera were obtained from sham-operated or splenectomized DBA/2 and C57BL/6 mice on Days 11, 18, and 24 after infection with nonlethal P. yoelii 17x and used to precipitate metabolically radiolabeled parasite antigens. Mice of both strains responded to many antigens. However, only splenectomized DBA/2 mice made strong antibody responses to antigens of approximately 110, 56, 50, 40, 35, and 20 kDa. Metabolically radiolabeled parasite extracts prepared in sham-operated and splenectomized mice appeared identical on SDS-PAGE. Thus it is unlikely that expression of new parasite antigens in splenectomized DBA/2 mice accounts for these results. Parasite-reactive IgM and IgG antibody responses were also modulated by splenectomy. Levels of IgM increased in splenectomized DBA/2 mice and decreased in C57BL/6 mice. Both mouse strains had slight to moderate increases in IgG when infected after splenectomy. The results suggest that when the spleen is present, responses to specific antigens are markedly suppressed. Alternatively, it is possible that in the absence of a spleen, antigen processing and presentation occurs in other tissues such as the lymph nodes or liver, leading to responses that are qualitatively different than those which occur when the spleen is present.