CTLA-4-dependent mechanisms prevent T cell induced-liver pathology during the erythrocyte stage of Plasmodium berghei malaria.

During the course of malaria several organs develop pathology. Frequently also signs of hepatocyte damage are found. In the present work we studied the mechanisms leading to liver pathology during the erythrocyte stage of Plasmodium berghei malaria. During infection, mice developed an inflammation of the liver, associated with infiltration of T cells, although only little tissue damage could be observed. Histological analysis revealed the presence of CTL-associated antigen-4 (CTLA-4)-positive T cells in the liver parenchyma. To study the influence of CTLA-4 expression on liver inflammation, mice were treated with an antibody against CTLA-4. Treated mice suffered from a dramatically increased liver pathology. Using cytokine-deficient mice we found that pathology was dependent on the presence of IL-12 and IFN-gamma. To further study the mechanisms that lead to an enhanced pathology, we analyzed cytokine production from liver-derived T cells. In infected mice the frequency of IFN-gamma-producing cells in the liver was low. In contrast, in anti-CTLA-4-treated mice larger numbers of IFN-gamma-producing cells were detectable. Our results indicate that activated T cells during the erythrocyte stage of malaria can induce pathology due to secretion of pro-inflammatory cytokines. Moreover, these results provide evidence that CTLA-4 expression can restrict T cell function in inflamed organs and might therefore prevent pathology.