Dendritic cells, pro-inflammatory responses, and antigen presentation in a rodent malaria infection.

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.

Disulfide bonds in merozoite surface protein 1 of the malaria parasite impede efficient antigen processing and affect the in vivo antibody response.

The 19 kDa C-terminal fragment of the malaria parasite merozoite surface protein 1 (MSP1(19)) is a leading malaria vaccine candidate. In rodents, high antibody levels to this protein confer protective immunity, and can be generated by immunization with the antigen in adjuvants. In natural human infections, however, MSP1(19)-specific antibody responses can be short-lived and comparatively low, despite repeated exposure to infection. The tightly folded structure of MSP1(19) is stabilized by five or six disulfide bonds. These bonds impede antigen processing and, thereby, may affect the generation of CD4+ T cells providing help for B cells. Asparagine endopeptidase could digest unfolded, but not native MSP1(19) in vitro. Immunization with unfolded MSP1(19) resulted in a faster antibody response, and a combination of unfolded and native MSP1(19) increased antibody responses to the native form. Immunization with either form of the antigen activated similar numbers of CD4+ T cells, but, unlike the antibody response, CD4+ T cells immunized with one form of MSP119 were able to respond in vitro to the other form of the protein. Although the reduced form of MSP1(19) does not induce protective antibodies, our data suggest that inclusion of unfolded protein may improve the efficacy of MSP1(19) as a vaccine.

CD8+ T cell-mediated suppression of intracellular Mycobacterium tuberculosis growth in activated human macrophages.

Animal models of tuberculosis point to a protective role for MHC class I-restricted CD8(+) T cells, yet it is unclear how these cells protect or whether such findings extend to humans. Here we report that macrophages infected with Mycobacterium tuberculosis, rapidly process and present an early secreted antigenic target (ESAT-6)-specific HLA class I-restricted CD8(+) T cell epitope. When cocultured with CD8(+) T cells restricted through classical HLA class I molecules the growth of bacilli within macrophages is significantly impaired after 7 days. This slow antimycobacterial activity did not correlate with macrophage lysis but required cell contact. We also found that inhibitors of apoptosis either had no effect or augmented the CD8-mediated suppressive activity, suggesting that an activation signal might be involved. Indeed we show that CD8(+) T cells were able to activate macrophages through receptors that include CD95 (Fas). Consistent with these findings the CD8-mediated suppression of mycobacterial growth was partially reversed by Fas blockade. These data identify a previously unrecognized CD8(+) T cell-mediated mechanism used to control an intracellular infection of macrophages.