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

Nat Immunol. 2011 Dec 11;13(2):188-95. doi: 10.1038/ni.2180.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • CD4-Positive T-Lymphocytes / drug effects*
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / parasitology
  • Child
  • Child, Preschool
  • Chronic Disease
  • Erythrocytes / immunology
  • Erythrocytes / parasitology
  • Female
  • Germinal Center / drug effects
  • Germinal Center / immunology
  • Germinal Center / parasitology
  • Humans
  • Lymphocyte Activation Gene 3 Protein
  • Malaria, Falciparum / drug therapy*
  • Malaria, Falciparum / immunology
  • Mali
  • Mice
  • Mice, Inbred C57BL
  • Plasmodium falciparum / drug effects*
  • Plasmodium falciparum / immunology
  • United States
  • Up-Regulation / drug effects

Substances

  • Antigens, CD
  • B7-H1 Antigen
  • CD274 protein, human
  • Cd274 protein, mouse
  • Lymphocyte Activation Gene 3 Protein