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

Abstract

Plasmodium infection of erythrocytes induces clinical malaria. Parasite-specific CD4+ T cells correlate with reduced parasite burdens and severity of human malaria, and are required 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 P. falciparum infection of humans increased expression of an inhibitory receptor (PD-1) associated with T cell dysfunction. In vivo blockade of PD-L1 and LAG-3 restored CD4+ T cell function, amplified T follicular helper cell and germinal center B cell and plasmablast numbers, enhanced protective antibodies and rapidly cleared blood-stage malaria in mice. Thus, chronic malaria drives specific T cell dysfunction, which can be rescued to enhance parasite control using inhibitory therapies.

Combination of 4-1BB Agonist and PD-1 Antagonist Promotes Antitumor Effector/Memory CD8 T Cells in a Poorly Immunogenic Tumor Model

“…To treat IFNg-deficient mice, antibodies were given three times 3 days apart. To deplete CD8 þ T cells, anti-CD8 (53.5.8, BioXcell) was given as described previously (22). Briefly, depleting antibody (100 mg) was administrated 1 day before anti-4-1BB/anti-PD-1 administration and every 5 days thereafter for a total of three doses.…”

The Upregulation of LAG-3 on T Cells Defines a Subpopulation with Functional Exhaustion and Correlates with Disease Progression in HIV-Infected Subjects

“…In a murine transplantable tumor model, it was observed that PD-1 and LAG-3 were coexpressed on tumor-infiltrating CD4 + and CD8 + T cells (23). Plasmodium infection induced T cell exhaustion, which could be restored by the blockade of PD ligand 1 (PD-L1) and LAG-3 in vivo; blocking PD-L1 and LAG-3 restored CD4 + T cell function, amplified the numbers of follicular helper T cells, enhanced protective Abs, and rapidly cleared the established bloodstage Plasmodium infection in mice (25). LAG-3 also defines an active CD4 + CD25 high Foxp3 + regulatory T cell subset, the fre-quency of which is enhanced in the PBMCs of cancer patients (26).…”

The Transcription Factor NFAT1 Participates in the Induction of CD4+T Cell Functional Exhaustion during Plasmodium yoelii Infection

“…Following 3 weeks of infection, mice were sacrificed and CD4 ϩ T cells were isolated from spleens. CD11a high CD49d ϩ staining has been shown to delineate previously activated CD4 ϩ T cells from naive cells in Plasmodium-infected mice (4,19) and therefore represent T cells that are likely to respond to a variety of Plasmodium antigens. We compared the responses and phenotypes of the CD4 ϩ CD11a high CD49d ϩ T cell populations from wild-type and Nfat1 Ϫ/Ϫ naive mice with those from mice infected with P. yoelii 17XNL.…”

“…To determine if NFAT1 could also play a role in controlling the exhaustion of T cells, we infected wild-type and Nfat1 Ϫ/Ϫ mice with Plasmodium yoelii 17XNL. Infection with this parasite had been previously shown to induce potent exhaustion of CD4 ϩ T cells (4). Following 3 weeks of infection, mice were sacrificed and CD4 ϩ T cells were isolated from spleens.…”

“…CD4 ϩ T cells are critical for the formation and maintenance of productive memory CD8 ϩ T cells, but they also contribute to the changes that occur in CD8 ϩ memory T cell populations during chronic infection (2,3). A hallmark of T cell exhaustion is the increased expression of coinhibitory surface molecules on exhausted T cells, and the exhaustion phenotype can be reversed through the blockade of those receptors (4)(5)(6). The involvement of several transcription factors, such as Blimp-1 and T-bet, in the induction of T cell exhaustion has been reported (7,8), but the mechanisms that underlie the transcriptional regulation of the many exhaustion molecules and phenotypes have not been fully elucidated.…”