Regulatory T cells impede acute and long-term immunity to blood-stage malaria through CTLA-4

Nat Med. 2017 Oct;23(10):1220-1225. doi: 10.1038/nm.4395. Epub 2017 Sep 11.


Malaria, caused by the protozoan Plasmodium, is a devastating mosquito-borne disease with the potential to affect nearly half the world's population. Despite mounting substantial T and B cell responses, humans fail to efficiently control blood-stage malaria or develop sterilizing immunity to reinfections. Although forkhead box P3 (FOXP3)+CD4+ regulatory T (Treg) cells form a part of these responses, their influence remains disputed and their mode of action is unknown. Here we show that Treg cells expand in both humans and mice in blood-stage malaria and interfere with conventional T helper cell responses and follicular T helper (TFH)-B cell interactions in germinal centers. Mechanistically, Treg cells function in a critical temporal window to impede protective immunity through cytotoxic-T-lymphocyte-associated protein-4 (CTLA-4). Targeting Treg cells or CTLA-4 in this precise window accelerated parasite clearance and generated species-transcending immunity to blood-stage malaria in mice. Our study uncovers a critical mechanism of immunosuppression associated with blood-stage malaria that delays parasite clearance and prevents development of potent adaptive immunity to reinfection. These data also reveal a temporally discrete and potentially therapeutically amenable functional role for Treg cells and CTLA-4 in limiting antimalarial immunity.

Publication types

  • Video-Audio Media

MeSH terms

  • Animals
  • CTLA-4 Antigen / immunology*
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • Germinal Center / immunology
  • Humans
  • Immune Tolerance / immunology
  • Lymph Nodes / pathology
  • Malaria / immunology*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Parasitemia / immunology*
  • Spleen / pathology
  • T-Lymphocytes, Helper-Inducer / immunology*
  • T-Lymphocytes, Regulatory / immunology*


  • CTLA-4 Antigen