T Cells and Immunity to the Asexual Blood Stages of Plasmodium chabaudi chabaudi CB

It is now clear that the major protective immune mechanisms to the erythrocytic stages of Plasmodium chabaudi chabaudi AS require the presence of CD4+ T lymphocytes. Both TH1 and TH2 malaria-specific, cloned T cell lines can protect immunocompromised mice upon adoptive transfer. Infection with P. c. adami, however, another subspecies of P. chabaudi, is thought to be resolved solely by antibody-independent mechanisms. In different host/parasite combinations, therefore, CD4-bearing lymphocytes mediate cellular protective functions and/or act as helper cells in protective antibody production. In addition, one report suggests that infection with P. c. chabaudi CB is controlled in an antibody-independent manner. Experiments were performed, therefore, to define further the role of T cells in immunity to rodent malaria using the CB strain of P. c. chabaudi in NIH mice. Although this strain is a virulent but usually resolving mouse malaria, it is often necessary to treat mice at the peak parasitaemia with subcurative doses of chloroquine. Such treatment, therefore, also allowed the effect of chemotherapy on the development of an immune response to be investigated. Using the P. c. chabaudi CB/NIH mouse system, selective depletion of T cell subsets by treatment with rat monoclonal antibodies to murine CD4 and CDS determinants revealed that the CD4-bearing population of lymphocytes is critically required for protection against erythrocytic infection. Mice lacking a CD4+ cell compartment suffered very high primary parasitaemias, that recurred despite treatment of the mice with chloroquine on days 8 and 9 post infection. For 30 days post infection (DPI) parasitaemias were never reduced below 3% and mice developed complications of infection such as ascites and subcutaneous oedema. In contrast, the parasitaemias of mice after removal of CD8-bearing lymphocytes did not deviate from the parasitaemias of immunocompetent control animals, although in mice lacking both CD4+ and CD8+ T cells the parasitaemias were higher than in mice depleted of CD4+ cells alone. This experiment demonstrated the crucial role that is played by P. c. chabaudi CB-specific CD4+ lymphocytes in the protective immune response to the asexual erythrocytic stages of this malaria parasite. Adoptive transfer experiments in vivo were carried out to determine if protection could be transferred with specific populations of enriched splenic lymphocytes, alone or in combination. Sublethally irradiated mice that received splenic cells taken from donor mice after clearance of a malarial infection (75 DPI) demonstrated a reduced level and quickened remission of primary parasitaemia and more rapid clearance of pRBCs from the bloodstream without recrudescence of infection, compared to control mice receiving unprimed splenic lymphocytes. Transfers carried out 21 DPI when the primary patent parasitaemia was subpatent, resulted in the same pattern of protection by T cells and a population of unfractionated cells, although the transfer of B cells did not prevent a recrudescence from occurring. Splenic T cells, therefore, from donor mice 21 DPI produced a sterilising immunity which appeared to transcend antigenic variation. When donor mice were treated with a subcurative dose of chloroquine 10 DPI the ability of 75 DPI spleen cells to confer a similar level of protection was not affected. When T, B and unfractionated cells were taken from chloroquine treated donor mice at the time of subpatency (14 DPI) and adoptively transferred into irradiated recipients, they were able to confer a level of protection which was demonstrated by a reduced peak parasitaemia, quickened pRBC remission and a prolonged subpatent period compared to the transfer of naive spleen cells, but in each case a recrudescence did occur. In all the transfers carried out, although it was possible to transfer immunity with preparations enriched for either T or B cells, optimal protection was conferred by an unfractionated population containing both lymphocyte phenotypes, suggesting that there was a degree of synergistic activity between parasite-primed T and B cells in the control of malarial infection. (Abstract shortened by ProQuest.)