Infective Dose Modulates the Balance between Th1- and Th2-Regulated Immune Responses during Blood-Stage Malaria Infection

Plasmodium chabaudi infection of mice provides an excellent model for examining acquired immunity to the blood-borne stage of malaria infection. CD4⁺ T-cell receptor (TCR) αβ-bearing T lymphocytes play a critical role in mediating protection, ascribed to both T helper (Th) 1 and Th2 subsets. One factor that may influence the Th1/Th2 cell balance is infective dose. In this study, we found that the size of the infective dose of P. chabaudi , and thus the level of antigen presented to the immune system, correlated with the balance of responder CD4⁺ T-cell phenotypes. Increasing the infective dose in a resistant mouse strain enhanced the Th1 cytokine (interferon-γ; IFN-γ) response and reduced the Th2 cytokine (interleukin-4; IL-4) response. In contrast, increasing the infective dose in a susceptible mouse strain led to a prominent and accelerated up-regulation of IL-4 production. These data show that the dose of antigen can significantly affect the balance between Th1- and Th2-mediated immune functions during infection of the mammalian host with blood-stage malaria parasites. This demonstration that parasite numbers may modulate CD4⁺ T-cell regulation has novel implications for the successful implementation of antimalarial vaccination and chemotherapeutic strategies.