Malaria parasite‐specific Th1‐like T cells simultaneously reduce parasitemia and promote disease

Abstract

CD4+ T cells have been implicated in immunity to the blood stages of malaria and cytokines associated with both monocyte and T cell activation have been implicated in disease. To determine whether specific T cells capable of inhibiting parasite growth can also mediate pathology we have transfused populations of Plasmodium berghei-specific T cells into normal and immunodeficient naive mice. We observed that they could inhibit parasite growth but were unable to save the animals which exhibited significantly greater anaemia and weight loss than control infected animals receiving either no T cells or T cells specific for ovalbumin. T cell-dependent tomour necrosis factor (TNF)alpha was a critical component in both parasite killing and disease promotion. Experiments with blocking antibodies demonstrated that all T-cell mediated antiparasitic immunity and all T-cell mediated weight loss was TNF-dependent. Blocking TNF-alpha in mice that received parasite-specific T cells prolonged the survival of the mice. Nitric oxide demonstrated no antiparasite effect, but was involved in the regulation of T-cell mediated weight loss. The data thus show that while parasite-specific CD4+ T cells can significantly limit parasite growth, such an effect need not be beneficial to the host, and that TNF-alpha and nitric oxide are critical effector molecules operating downstream of parasite-specific T cells in both immunity and disease.

Global Gene Expression Profiles During Acute Pathogen-Induced Pulmonary Inflammation Reveal Divergent Roles for Th1 and Th2 Responses in Tissue Repair

“…Consistent with the enhanced acute-phase response, mice with a polarized Th1 response show marked weight loss relative to infected wild-type mice upon infection with a variety of pathogens, including S. mansoni and Plasmodium berghei (25)(26)(27). In addition to cachexia, mice infected with P. berghei in a Th1 environment suffered extensive coagulative necrosis of the liver despite lower parasitemia, and IL-10/4 KO mice infected with S. mansoni had significantly more hepatotoxicity, reflected by elevated aminotransferase levels (26,27).…”

Murine Malaria Is Exacerbated by CTLA-4 Blockade

“…The role of CD4 ϩ T cells during the blood stage of infection is not completely clear, but many examples demonstrate the importance of CD4 ϩ T cells in the control of blood-stage malaria (1). However, it was shown that P. berghei-specific CD4 ϩ T cells have the ability to promote disease (5,11,37). Symptoms were attenuated by immunosuppressive drugs (38,39) or by removing the thymus (40).…”

“…Therefore, a direct interaction of T cells and parasites or infected cells is unlikely. However, the contribution of CD4 ϩ T cells in acquired immunity to blood-stage malaria was demonstrated using several strains of Plasmodium parasites in mice (1)(2)(3)(4)(5). These studies suggested that malaria-specific T cells, especially cytokine-secreting Th1 cells, regulate other antiparasitic effector systems.…”

Identification of T Cell Epitopes on the 33-kDa Fragment of Plasmodium yoelii Merozoite Surface Protein 1 and Their Antibody-Independent Protective Role in Immunity to Blood Stage Malaria

“…This approach was followed because we (19,20) and others (21) have shown that T cells can adoptively transfer protection to malaria and because it is possible that the vaccination protocol (above) was unable to induce sufficient numbers of T cells. Furthermore, the phenotypes of vaccine-induced T cells is likely to be heterogeneous.…”