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London School of Hygiene & Tropical Medicine Malaria Centre

Malaria research in immunology and vaccination

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

LSHTM investigators:
Julius Hafalla, Kevin Couper & Eleanor Riley.
External collaborators:
Brian de Souza (University College, London); Carla Claser & Laurent Renia (Singapore Immunology Network, Singapore); Georges Grau (The University of Sydney, Australia).
Funding body:
Wellcome Trust and The Royal Society.

The balance between pro-inflammatory and regulatory immune responses in determining optimal T cell activation is vital for the successful resolution of malaria infections.

During chronic infections, this balance is maintained in part by the negative regulators of T cell activation, CTLA-4 and PD-1/PD-L1, which dampen effector responses. However, their role in acute infections, such as malaria, remains less clear. Thus, 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. 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-g 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-g 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.