The CTLA-4 and PD-1/PD-L1 inhibitory pathways independently regulate host resistance to Plasmodium-induced acute immune pathology

• Published in: PLoS pathogens Vol. 8; no. 2; p. e1002504
• Main Authors: Hafalla, Julius Clemence R, Claser, Carla, Couper, Kevin N, Grau, Georges Emile, Renia, Laurent, de Souza, J Brian, Riley, Eleanor M
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.02.2012; Public Library of Science (PLoS)
• Subjects: Animals; Antigens, Differentiation - immunology; Antigens, Differentiation - metabolism; B7-H1 Antigen - immunology; B7-H1 Antigen - metabolism; Biology; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; CTLA-4 Antigen - immunology; CTLA-4 Antigen - metabolism; Erythrocytes - parasitology; Health aspects; Host-parasite relationships; Immunology; Interferon-gamma - immunology; Lymphocyte Activation - immunology; Malaria, Cerebral - immunology; Malaria, Cerebral - microbiology; Malaria, Cerebral - pathology; Medicine; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Parasites; Pathology; Physiological aspects; Physiology, Pathological; Plasmodium; Plasmodium berghei - immunology; Plasmodium berghei - pathogenicity; Programmed Cell Death 1 Receptor; Rodents; T cell receptors; United Kingdom
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1002504

The balance between pro-inflammatory and regulatory immune responses in determining optimal T cell activation is vital for the successful resolution of microbial infections. This balance is maintained in part by the negative regulators of T cell activation, CTLA-4 and PD-1/PD-L, which dampen effector responses during chronic infections. However, their role in acute infections, such as malaria, remains less clear. In this study, we determined the contribution of CTLA-4 and PD-1/PD-L to the regulation of T cell responses during Plasmodium berghei ANKA (PbA)-induced experimental cerebral malaria (ECM) in susceptible (C57BL/6) and resistant (BALB/c) mice. We found that the expression of CTLA-4 and PD-1 on T cells correlates with the extent of pro-inflammatory responses induced during PbA infection, being higher in C57BL/6 than in BALB/c mice. Thus, ECM develops despite high levels of expression of these inhibitory receptors. However, antibody-mediated blockade of either the CTLA-4 or PD-1/PD-L1, but not the PD-1/PD-L2, pathways during PbA-infection in ECM-resistant BALB/c mice resulted in higher levels of T cell activation, enhanced IFN-γ production, increased intravascular arrest of both parasitised erythrocytes and CD8(+) T cells to the brain, and augmented incidence of ECM. Thus, in ECM-resistant BALB/c mice, CTLA-4 and PD-1/PD-L1 represent essential, independent and non-redundant pathways for maintaining T cell homeostasis during a virulent malaria infection. Moreover, neutralisation of IFN-γ or depletion of CD8(+) T cells during PbA infection was shown to reverse the pathologic effects of regulatory pathway blockade, highlighting that the aetiology of ECM in the BALB/c mice is similar to that in C57BL/6 mice. In summary, our results underscore the differential and complex regulation that governs immune responses to malaria parasites.