Therapeutic blockade of PD-L1 and LAG-3 rapidly clears established blood-stage Plasmodium infection

• Published in: Nature immunology Vol. 13; no. 2; pp. 188 - 195
• Main Authors: Butler, Noah S, Moebius, Jacqueline, Pewe, Lecia L, Traore, Boubacar, Doumbo, Ogobara K, Tygrett, Lorraine T, Waldschmidt, Thomas J, Crompton, Peter D, Harty, John T
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.02.2012; Nature Publishing Group
• Subjects: 631/250/1619/554/1898; 631/250/255/1629; 692/700/565; Acute Disease; Animals; Antigens, CD - drug effects; Antigens, CD - immunology; B-Lymphocytes - drug effects; B-Lymphocytes - immunology; B-Lymphocytes - parasitology; B7-H1 Antigen - antagonists & inhibitors; B7-H1 Antigen - immunology; Biomedical and Life Sciences; Biomedicine; Blood; Causes of; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - parasitology; Child; Child, Preschool; Chronic Disease; Development and progression; Erythrocytes; Erythrocytes - immunology; Erythrocytes - parasitology; Female; Germinal Center - drug effects; Germinal Center - immunology; Germinal Center - parasitology; Health aspects; Humans; Immunology; Infectious Diseases; Malaria; Malaria, Falciparum - drug therapy; Malaria, Falciparum - immunology; Mali; Mice; Mice, Inbred C57BL; Parasite control; Plasmodium falciparum; Plasmodium falciparum - drug effects; Plasmodium falciparum - immunology; Prevention; T cells; United States; Up-Regulation - drug effects; Vector-borne diseases; United States
• ISSN: 1529-2908; 1529-2916
• DOI: 10.1038/ni.2180

Chronically infected mice upregulate expression of inhibitory molecules on exhausted T cells. Harty and colleagues report similar findings in human patients with malaria and show that blockade of the inhibitory receptors PD-L1 and LAG-3 restores antimalaria responses in mice. 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.