Therapeutic blockade of PD-L1 and LAG-3 rapidly clears established blood-stage Plasmodium infection
Noah S Butler, Jacqueline Moebius, Lecia L Pewe, Boubacar Traore, Ogobara K Doumbo, Lorraine T Tygrett, Thomas J Waldschmidt, Peter D Crompton, John T Harty, Noah S Butler, Jacqueline Moebius, Lecia L Pewe, Boubacar Traore, Ogobara K Doumbo, Lorraine T Tygrett, Thomas J Waldschmidt, Peter D Crompton, John T Harty
Abstract
Infection of erythrocytes with Plasmodium species induces clinical malaria. Parasite-specific CD4(+) T cells correlate with lower parasite burdens and severity of human malaria and are needed to control blood-stage infection in mice. However, the characteristics of CD4(+) T cells that determine protection or parasite persistence remain unknown. Here we show that infection of humans with Plasmodium falciparum resulted in higher expression of the inhibitory receptor PD-1 associated with T cell dysfunction. In vivo blockade of the PD-1 ligand PD-L1 and the inhibitory receptor LAG-3 restored CD4(+) T cell function, amplified the number of follicular helper T cells and germinal-center B cells and plasmablasts, enhanced protective antibodies and rapidly cleared blood-stage malaria in mice. Thus, chronic malaria drives specific T cell dysfunction, and proper function can be restored by inhibitory therapies to enhance parasite control.
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References
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Source: PubMed