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

doi:10.1038/ni.2180

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

Journal article

Peer reviewed

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 and John T Harty

Nature immunology, Vol.13(2), pp.188-195

12/11/2011

DOI: 10.1038/ni.2180

PMCID: PMC3262959

PMID: 22157630

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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.

Antigens, CD - immunology

United States

Germinal Center - immunology

Humans

B-Lymphocytes - parasitology

Child, Preschool

Germinal Center - drug effects

Plasmodium falciparum - drug effects

Plasmodium falciparum - immunology

CD4-Positive T-Lymphocytes - parasitology

CD4-Positive T-Lymphocytes - immunology

Mali

Female

Child

Germinal Center - parasitology

Erythrocytes - immunology

Malaria, Falciparum - drug therapy

Acute Disease

Mice, Inbred C57BL

Antigens, CD - drug effects

B7-H1 Antigen - immunology

Up-Regulation - drug effects

B-Lymphocytes - drug effects

Animals

B-Lymphocytes - immunology

B7-H1 Antigen - antagonists & inhibitors

Malaria, Falciparum - immunology

Mice

Erythrocytes - parasitology

Chronic Disease

CD4-Positive T-Lymphocytes - drug effects

Details

Title: Subtitle: Therapeutic blockade of PD-L1 and LAG-3 rapidly clears established blood-stage Plasmodium infection
Creators: Noah S Butler - Department of Microbiology, University of Iowa, Iowa City, Iowa, USA
Jacqueline Moebius
Lecia L Pewe
Boubacar Traore
Ogobara K Doumbo
Lorraine T Tygrett
Thomas J Waldschmidt
Peter D Crompton
John T Harty
Resource Type: Journal article
Publication Details: Nature immunology, Vol.13(2), pp.188-195
DOI: 10.1038/ni.2180
PMID: 22157630
PMCID: PMC3262959
NLM abbreviation: Nat Immunol
ISSN: 1529-2916
eISSN: 1529-2916
Publisher: United States
Grant note: Intramural NIH HHS R37 AI042767-14 / NIAID NIH HHS AI085515 / NIAID NIH HHS R37 AI042767 / NIAID NIH HHS R01 AI085515-01A1 / NIAID NIH HHS AI42767 / NIAID NIH HHS R01 AI042767 / NIAID NIH HHS R01 AI085515 / NIAID NIH HHS R21 AI042767 / NIAID NIH HHS
Language: English
Date published: 12/11/2011
Academic Unit: Microbiology and Immunology; Pathology
Record Identifier: 9984001145802771

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