In vitro and in vivo effect of PD‐1/PD‐L1 blockade on microglia/macrophage activation and T cell subset balance in cryptococcal meningitis

Abstract

This study aimed to investigate the PD-1/ PD-L1 signaling pathway and its effects the activation of microglia/macrophage and balancing T cell subsets in cryptococcal meningitis (CM). A total of 126 CM patients and 126 healthy individuals were recruited for the study. The CM patients were treated with amphotericin B (AmB). Seventy five C57BL/6 mice were grouped into the normal control, CM model, CM + AmB, sham, and CM + PD-1 antibodies (Ab) groups. CD4 and CD8 T cells as well as microglia/macrophages were analyzed by means of flow cytometry. Ionized calcium-binding adaptor molecule 1 (Ibal) expression was detected using western blotting and immunohistochemistry techniques. And the expression of Rab5 and Rab11 were detected using an immunofluorescence assay. Both PD-1 and PD-L1 mRNA and protein expression among the mice in the study were evaluated by qRT-PCR and western blotting methods. Compared to the CM model group, the CM + AmB and CM + PD-1 Ab groups exhibited increased levels of Th1 cytokines and chemokines expression, and reduced levels of Th2 cytokines expressions. Elevated cell purity and viability of CD4 T cell were recorded as well as increases in microglia, however, there were reductions in the number of CD8 T cells. Depleted expressions of Ibal, Rab5, and Rab11 as well as reduced mRNA expressions of PD-1 and PD-L1 in CD4 , microglia, and macrophage cells. The findings suggested that suppression of the PD-1/PD-L1 signaling pathway restricts the proliferation of CM by down-regulating the expressions of Th2 cells and suppressing microglia and macrophage activation.

PD-L1 negatively regulates antifungal immunity by inhibiting neutrophil release from bone marrow

“…Coincidentally, recent studies have shown that, PD-L1 expression in DCs induced by α-(1,3)-glucan from Aspergillus fumigatus through activating Wnt/β-catenin pathway promotes regulatory T-cell (Treg) polarization, suggesting that PD-L1 in DCs negatively regulates α-(1,3)-glucan-induced protective immune responses against A. fumigatus infection 43 , 44 . Moreover, it has been further reported that, PD-L1 expression in macrophages induced by Cryptococcus neoformans infection suppresses macrophage activation, and PD-L1 expression in T cells induced by C. albicans infection can promote T cell exhaustion 19 , 45 . It remains unclear whether PD-L1 expression in neutrophils induced by β-glucans can affect Treg polarization, macrophage activation or T cell exhaustion during C. albicans infection, which would be further explored in our future studies.…”

The Emerging Role of Rab5 in Membrane Receptor Trafficking and Signaling Pathways

“…e reduced activity of Rab5 inhibits TCR degradation and enhances TCR signaling pathways. In mouse 2 cells, knockdown of Rab5 selectively affects TCR downstream signaling and promotes the production of the corresponding cytokines [105]. It was reported that the number of CD4 + CD8 + thymocytes is obviously reduced in T-cell-specific Rab5-N133I transgenic mice, suggesting that Rab5 plays a key role in TCR transport and signal transduction [106].…”

Landmark clinical observations and immunopathogenesis pathways linked to HIV and Cryptococcus fatal central nervous system co‐infection

“…In mouse models of cryptococcosis, persistent lung infection sustains PD‐1 expression on dendritic cells and on macrophages 73 . Moreover, sustained PD‐1 expression on the macrophages on cryptococcosis brain mouse models promotes fungal growth through upregulated proliferation of Cryptococcus ‐infected macrophages, facilitating fungal dissemination 73,78 . The PD‐1 upregulation further increases activation of microglial cells and promotes Th2 cellular‐activated responses while downregulating Th1‐activated responses 78 .…”

“…73 Moreover, sustained PD-1 expression on the macrophages on cryptococcosis brain mouse models promotes fungal growth through upregulated proliferation of Cryptococcus-infected macrophages, facilitating fungal dissemination. 73,78 The PD-1 upregulation further increases activation of microglial cells and promotes Th2 cellular-activated responses while downregulating Th1-activated responses. 78 Of note, application of anti-PD-1/PD-L1 antagonists (PD-1 blocking antibodies) altered PD-1-modulated responses by promoting fungal clearance, upregulating ICOS and XO40 on Th1, Th2, Th17 and regulatory T cells while downregulating IL-5 and IL-10 immune regulatory cytokines in the model of cryptococcosis.…”

“…73,78 The PD-1 upregulation further increases activation of microglial cells and promotes Th2 cellular-activated responses while downregulating Th1-activated responses. 78 Of note, application of anti-PD-1/PD-L1 antagonists (PD-1 blocking antibodies) altered PD-1-modulated responses by promoting fungal clearance, upregulating ICOS and XO40 on Th1, Th2, Th17 and regulatory T cells while downregulating IL-5 and IL-10 immune regulatory cytokines in the model of cryptococcosis. 73 In addition, similar responses were observed with IL-10 blockade in experimental cryptococcal infection.…”