B-CELLS ARE REQUIRED FOR THE SWITCH FROM TH1-REGULATED TO TH2-REGULATED IMMUNE-RESPONSES TO PLASMODIUM-CHABAUDI-CHABAUDI INFECTION

The induction of T-helper cell subsets during the course of blood stag e Plasmodium chabaudi chabaudi infection was compared in immunological ly intact NIH mice and mice that were depleted of B cells from birth b y treatment with anti-p antibodies. for intact mice, in which the acut e primary parasitemia peaked 10 days following infection, purified spl enic CD4(+) T cells recovered during the ascending parasitemia produce d high levels in vitro of interleukin 2 (IL-2) (peak levels on day 10) and gamma interferon (IFN-gamma) (peak levels on day 7). Sera collect ed from these mice at around this time contained relatively high level s of P. c. chabaudi-specific immunoglobulin 2a (peak levels on day 12) , and serum nitric oxide activity was significantly elevated at peak p arasitemia. During the descending primary parasitemia, production of I FN-gamma and IL-2 decreased, while levels of IL-4 and IL-10 produced b y splenic CD4(+) T cells were significantly raised from the time at wh ich subpatency was recorded (day 17) and persisted for at least 50 day s. This was concomitant with a significant increase in levels of paras ite-specific immunoglobulin GL, which peaked at around the time of rec rudescence. Thus, in normal mice, sequential appearance of Th1 and Th2 responses was observed. In contrast, in B-cell-depleted mice, recover y from acute primary parasitemia was followed by a persistent patent i nfection which did not drop below 0.1% for at least 75 days after init iation of infection. These mice were unable to mount a significant Th2 response, manifest as an enduring inability of splenic CD4(+) T cells to produce significant levels of IL-4 and IL-10. IL-2 and IFN-gamma l evels remained significantly elevated throughout the 50-day observatio n period, and there was sustained production of nitric oxide. These da ta show that immune responses mediated by CD4(+) T cells of the Th1 su bset are capable of limiting infection beyond the initial acute phase, but that they do not eliminate parasitemia. Furthermore, as the progr ession from a Th1-regulated to a Th2-regulated immune response fails t o occur in B-cell-depleted mice, the data suggest that B cells are req uired for the downregulation of Th1-mediated and/or the generation of Th2-mediated protective immunity to P. c. chabaudi.