Malaria-specific transgenic CD4+ T cells protect immunodeficient mice from lethal infection and demonstrate requirement for a protective threshold of antibody production for parasite clearance

Abstract

T cells are important in the immune response to malaria, both for their cytokines and their help for antibody production. To look at the relative importance of these roles, a T-cell receptor (TCR) transgenic mouse has been generated carrying a TCR specific for an epitope of the merozoite surface protein 1 (MSP-1) of the malaria parasite, Plasmodium chabaudi. In adoptive transfer experiments, malaria-specific CD4 ؉ T cells expand and produce interferon ␥ (IFN-␥) early in infection, but the population contracts quickly despite prolonged persistence of the parasite. MSP-1-specific CD4 ؉ cells can protect immunodeficient mice from lethal infection; however, the parasite is only completely cleared in the presence of B cells showing that T helper cells are critical. Levels of malariaspecific antibody and the speed of their production clearly correlate with the time of resolution of infection, indicating that a critical threshold of antibody production is required for parasite clearance. Furthermore, T cells specific for a shed portion of MSP-1 are able to provide help for antibody to the protective region, which remains bound to the infected erythrocyte, suggesting that MSP-1 has all of the components necessary for a good vaccine. IntroductionT helper cells are essential for a protective immune response to the blood stages of the rodent malaria parasite, Plasmodium chabaudi chabaudi (AS). 1 There is debate, however, over the extent to which T cells protect via Th1 cytokine-mediated mechanisms or by the antibodies that they help to produce. Both mechanisms dominate the T-cell response to P chabaudi in turn, with an early Th1-type cytokine response, which switches later in infection to one that provides effective help for malaria-specific antibody production and produces less interferon ␥ (IFN-␥). 2,3 Increased T-helper cell activity in the later stages 3 is clearly beneficial because experiments in B cell-deficient mice demonstrate that B cells and antibodies are required for complete clearance of parasites, 4-6 although the requirements and specificity of T-cell help and antibody for rapid clearance or immunity to reinfection are not known.To determine the precise role of malaria-specific T helper cells and the potential of an important vaccine antigen, merozoite surface protein 1 (MSP-1), in the protection from and clearance of malaria infection, we have generated a T-cell receptor (TCR) transgenic mouse with a TCR specific for P chabaudi MSP-1. This molecule is expressed on the invasive merozoite surface, 7 and its C-terminal domain can induce a protective immune response. [8][9][10][11] However, this domain is not efficiently processed by antigenpresenting cells and is a less effective inducer of CD4 ϩ T-cell responses than other parts of MSP-1. 10,12,13 For more effective vaccination strategies it would be important to know whether CD4 ϩ T-cell help can be generated from other parts of MSP-1, which are more readily processed and presented on antigenpresenting cells. The MSP-1-specific TCR of our transgenic mouse,...

Development of a Novel CD4+ TCR Transgenic Line That Reveals a Dominant Role for CD8+ Dendritic Cells and CD40 Signaling in the Generation of Helper and CTL Responses to Blood-Stage Malaria

“…Both B cells and Th cells are essential for the control of P. chabaudi parasitemia (61,62), and protection is mainly achieved by parasite-specific T cell-dependent Abs (17). This model was therefore ideally suited to test whether PbT-II cells have the capacity to provide protective immunity to malaria.…”

“…Cross-talk between CD4 + T cells and naive B cells resulting in Ig class switching is essential for the clearance of certain pathogens such as Plasmodium chabaudi AS. Thus, mice lacking CD4 + T cells or B cells are unable to control parasitemia in this model (17). Another important role for CD4 + T cells is the provision of help resulting in the licensing of dendritic cells (DC) for the effective priming of CD8 + T cells.…”

“…In this study, we describe an MHC class II (MHC II)-restricted (I-A b ) TCR murine line, termed PbT-II, that responds to a parasite Ag expressed across multiple rodent and human Plasmodium species, making it a general tool for studying malaria immunity in C57BL/6 (B6) mice. PbT-II TCR transgenic mice add to the existing I-E d -restricted B5 TCR transgenic mice (2,4,17) to extend the set of available tools for the analysis of CD4 + T cell responses to parasites during Plasmodium infection of B6 mice.…”

A role for CD4+ and CD8+ cells and not for CD25+ cells in the control ofPlasmodium bergheiAnka blood stage parasites in rats

“…1). It is well known that CD4+ T cells play a critical role in protective immunity to blood malaria parasites by expressing direct effector functions as well as by helping B cells for antibody production (Stephens et al, 2005). The role of CD4+ cells is also supported by the fact that human CD4+ T cells are able to inhibit blood parasites in vitro (Fell et al, 1994).…”

Early Treatment with Chloroquine Inhibits the Immune Response against<i> Plasmodium yoelii</i> Infection in Mice

“…Studies form both human malaria and the mouse model indicate that protective immunity against blood-stage Plasmodium infection requires activation of malaria-specific CD4 + T cells and the production of neutralizing antibodies (Stephens et al 2005). Dendritic cells (DCs) play a critical role in initiating adaptive immunity and shaping the type of T helper (Th) response.…”