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,...

An infection of mice with Plasmodium chabaudi is characterized by a rapid and marked inflammatory response with a rapid but regulated production of interleukin-12 (IL-12), tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma). Recent studies have shown that dendritic cells (DCs) are activated in vivo in the spleen, are able to process and present malaria antigens during infection, and may provide a source of cytokines that contribute to polarization of the CD4 T-cell response. P. chabaudi-infected erythrocytes are phagocytosed by DCs, and peptides of malaria proteins are presented on major histocompatibility complex (MHC) class II. The complex disulfide-bonded structure of some malaria proteins can impede their processing in DCs, which may affect the magnitude of the CD4 T-cell response and influence T-helper 1 (Th1) or Th2 polarization. DCs exhibit a wide range of responses to parasite-infected erythrocytes depending on their source, their maturational state, and the Plasmodium species or strain. P. chabaudi-infected erythrocytes stimulate an increase in the expression of costimulatory molecules and MHC class II on mouse bone marrow-derived DCs, and they are able to induce the production of pro-inflammatory cytokines such as IL-12, TNF-alpha, and IL-6, thus enhancing the Th1 response of naïve T cells. IFN-gamma and TNF-alpha play a role in both protective immunity and the pathology of the infection, and the inflammatory disease may be regulated by IL-10 and transforming growth factor-beta. It will therefore be important to elucidate the host and parasite molecules that are involved in activation or suppression of the DCs and to understand the interplay between these opposing forces on the host response in vivo during a malaria infection.

No abstract

Seqirus; Clinicaltrials.gov: NCT02214225.

Seqirus Pty Ltd; ClinicalTrials.gov identifier:NCT02914275.