Gammadelta T cells but not NK cells are essential for cell-mediated immunity against Plasmodium chabaudi malaria.

Blood-stage Plasmodium chabaudi infections are suppressed by antibody-mediated immunity and/or cell-mediated immunity (CMI). To determine the contributions of NK cells and γδ T cells to protective immunity, C57BL/6 (wild-type [WT]) mice and B-cell-deficient (J(H(-/-))) mice were infected with P. chabaudi and depleted of NK cells or γδ T cells with monoclonal antibody. The time courses of parasitemia in NK-cell-depleted WT mice and J(H(-/-)) mice were similar to those of control mice, indicating that deficiencies in NK cells, NKT cells, or CD8(+) T cells had little effect on parasitemia. In contrast, high levels of noncuring parasitemia occurred in J(H(-/-)) mice depleted of γδ T cells. Depletion of γδ T cells during chronic parasitemia in B-cell-deficient J(H(-/-)) mice resulted in an immediate and marked exacerbation of parasitemia, suggesting that γδ T cells have a direct killing effect in vivo on blood-stage parasites. Cytokine analyses revealed that levels of interleukin-10, gamma interferon (IFN-γ), and macrophage chemoattractant protein 1 (MCP-1) in the sera of γδ T-cell-depleted mice were significantly (P < 0.05) decreased compared to hamster immunoglobulin-injected controls, but these cytokine levels were similar in NK-cell-depleted mice and their controls. The time courses of parasitemia in CCR2(-/-) and J(H(-/-)) × CCR2(-/-) mice and in their controls were nearly identical, indicating that MCP-1 is not required for the control of parasitemia. Collectively, these data indicate that the suppression of acute P. chabaudi infection by CMI is γδ T cell dependent, is independent of NK cells, and may be attributed to the deficient IFN-γ response seen early in γδ T-cell-depleted mice.

CD28 costimulation is required for the expression of T-cell-dependent cell-mediated immunity against blood-stage Plasmodium chabaudi malaria parasites.

Mice suppress the parasitemia of acute blood-stage Plasmodium chabaudi malaria by an antibody- or T-cell-dependent cell-mediated mechanism of immunity (AMI and CMI, respectively) or by both mechanisms. To determine whether CD28 costimulation is required for expression of these polar immune responses, we first compared the time courses of P. chabaudi malaria in CD28-deficient (CD28(-/-)) and CD28-intact (CD28(+/+)) mice. Acute infections in both knockout (KO) and control mice followed similar time courses, with the period of descending parasitemia being prolonged approximately 2 weeks in KO mice followed by intermittent low-grade chronic parasitemia. Infected CD28(-/-) mice produced primarily the immunoglobulin M antibody, which upon passive transfer provided partial protection against P. chabaudi challenge, suggesting that the elimination of blood-stage parasites by CD28(-/-) mice was achieved by AMI. To determine whether CD28(-/-) costimulation is required for the expression of CMI against the parasite, we compared the time courses of parasitemia in B-cell-deficient double-KO (J(H)(-/-) x CD28(-/-)) mice and control (J(H)(-/-) x CD28(+/+)) mice. Whereas control mice suppressed parasitemia to subpatent levels within approximately 2 weeks postinoculation, double-KO mice developed high levels of parasitemia of long-lasting duration. Although not required for the suppression of acute P. chabaudi parasitemia by AMI, CD28 costimulation is essential for the elimination of blood-stage parasites by CMI.