Lymphocyte crosstalk is required for monocyte-intrinsic trained immunity to Plasmodium falciparum
Juliet N. Crabtree, Daniel R. Caffrey, Leandro de Souza Silva, Evelyn A. Kurt-Jones, Katherine Dobbs, Arlene Dent, Katherine A. Fitzgerald, Douglas T. Golenbock
Juliet N. Crabtree, Daniel R. Caffrey, Leandro de Souza Silva, Evelyn A. Kurt-Jones, Katherine Dobbs, Arlene Dent, Katherine A. Fitzgerald, Douglas T. Golenbock
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Research Article Immunology Infectious disease

Lymphocyte crosstalk is required for monocyte-intrinsic trained immunity to Plasmodium falciparum

Abstract

Plasmodium falciparum (P. falciparum) induces trained innate immune responses in vitro, where initial stimulation of adherent PBMCs with P. falciparum–infected RBCs (iRBCs) results in hyperresponsiveness to subsequent ligation of TLR2. This response correlates with the presence of T and B lymphocytes in adherent PBMCs, suggesting that innate immune training is partially due to adaptive immunity. We found that T cell–depleted PBMCs and purified monocytes alone did not elicit hyperproduction of IL-6 and TNF-α under training conditions. Analysis of P. falciparum–trained PBMCs showed that DCs did not develop under control conditions, and IL-6 and TNF-α were primarily produced by monocytes and DCs. Transwell experiments isolating purified monocytes from either PBMCs or purified CD4+ T cells, but allowing diffusion of secreted proteins, enabled monocytes trained with iRBCs to hyperproduce IL-6 and TNF-α after TLR restimulation. Purified monocytes stimulated with IFN-γ hyperproduced IL-6 and TNF-α, whereas blockade of IFN-γ in P. falciparum–trained PBMCs inhibited trained responses. Assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-Seq) on monocytes from patients with malaria showed persistently open chromatin at genes that appeared to be trained in vitro. Together, these findings indicate that the trained immune response of monocytes to P. falciparum is not completely cell intrinsic but depends on soluble signals from lymphocytes.

Authors

Juliet N. Crabtree, Daniel R. Caffrey, Leandro de Souza Silva, Evelyn A. Kurt-Jones, Katherine Dobbs, Arlene Dent, Katherine A. Fitzgerald, Douglas T. Golenbock

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Figure 2

Recent exposure of PBMCs to P. falciparum leads to a sustained immune response that is further amplified by PAM3CSK4.

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Recent exposure of PBMCs to P. falciparum leads to a sustained immune re...
(A) RNA expression of PBMCs recently exposed to infected and uninfected RBCs and subsequently stimulated with PAM3CSK4 (after 0 hours). RNA expression units correspond to transcripts per million (TPM) mapped reads. Each hexagonal bin shows the number of genes with the corresponding expression level. n = 3. (B) Significantly enriched GO terms (biological processes) among the 100 genes with the greatest fold change between PBMCs recently exposed to infected RBCs and PBMCs exposed to uninfected RBCs at 0 hours prior to PAM3CSK4 stimulation. Five GO terms of interest (red, blue, green, purple, and orange) were further examined in C. (C) Expression levels (TPM) among the 50 genes with the greatest fold change between PBMCs recently exposed to infected RBCs and PBMCs exposed to uninfected RBCs at 0 hours prior to PAM3CSK4 stimulation. Expression levels at 4 and 12 hours after PAM3CSK4 stimulation are also shown. Genes belonging to the 5 GO terms of interest (red, blue, green, purple, and orange) are indicated above the heatmap. The blue arrows indicate genes that are described in the main text. The red gene labels indicate genes that are shown in a subsequent ATAC-Seq experiment.