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PD-1 deficiency promotes TFH cells expansion in ITV-immunized mice by upregulating cytokines secretion.

ABSTRACT:

Background

T follicular helper (TFH) cells are fundamental for the development of humoral immunity. In our previous study, we found that PD-1 deficiency substantially promoted the expansion of Plasmodium-specific TFH cells and enhanced the humoral immunity of ITV (infection treatment vaccine)-immunized mice. However, the underlying mechanism by which PD-1 signaling modulates TFH cells activation remains unclear.

Methods

Mice were immunized with the ITV following the standard procedures. The activation phenotype of CD11c⁺CXCR5⁺ dendritic cells (DCs), the frequency and number of splenic follicular regulatory T cells (TFR cells), Plasmodium-specific TFH cells and germinal center (GC) B cells were analyzed by FACS. The levels of serum cytokines were quantified using the cytometric bead array (CBA) and in vivo cytokine neutralization was carried out according to a previously described protocol and verified by serum cytokine detection.

Results

We found that PD-1^-/- naïve and immunized mice had more TFR cells in the spleen than WT and WT immunized mice. Additionally, CXCR5⁺ DC, which prime TFH cells, were activated at similar levels in ITV-immunized WT and PD-1^-/- mice. However, the serum levels of IL-10, IFN-? and MCP-1 were significantly increased in ITV-immunized PD-1^-/- mice, and treatment with an anti-IL-10, anti-IFN-? or anti-MCP-1 neutralizing antibody in vivo markedly impaired the development of TFH cells and GC B cells.

Conclusions

Our findings demonstrate that the modulation of TFH cells by PD-1 signaling is dependent on the cytokines IL-10, IFN-? and MCP-1 in ITV-immunized mice. These results could facilitate the design of an effective malaria vaccine with the aim of inducing humoral immune responses.

SUBMITTER: Liu T

PROVIDER: S-EPMC6035468 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Publications

PD-1 deficiency promotes TFH cells expansion in ITV-immunized mice by upregulating cytokines secretion.

Liu Taiping T Cheng Xiangyun X Ding Yan Y Zhu Feng F Fu Yong Y Peng Xiaohong X Xu Wenyue W

Parasites & vectors 20180706 1

<h4>Background</h4>T follicular helper (TFH) cells are fundamental for the development of humoral immunity. In our previous study, we found that PD-1 deficiency substantially promoted the expansion of Plasmodium-specific TFH cells and enhanced the humoral immunity of ITV (infection treatment vaccine)-immunized mice. However, the underlying mechanism by which PD-1 signaling modulates TFH cells activation remains unclear.<h4>Methods</h4>Mice were immunized with the ITV following the standard proce ...[more]

PMID: 29980219

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Project description:Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor with poor prognosis, and currently effective therapeutic strategies are still limited. Although temozolomide (TMZ) is commonly used for GBM therapy and its mechanism was well characterized, while its side effects were required comprehensive investigation. In the present study, we revealed that TMZ-challenged GBM cells strongly suppressed pro-inflammatory cytokines expression in activated periphery blood mononuclear cells (PBMC), which depended on enhanced transcription of CD274 (encoding PD-L1), but not other immune checkpoints, such as CD276, HVEM and galectin-9. Moreover, abundance of membranous PD-L1 was also increased in TMZ-treated GBM cells. When PD-L1 expression was knocked down by short hairpin RNA (shRNA), inhibitory effect of TMZ-treated GBM cells on PBMC became weakened, suggesting that PD-L1 was crucial for immune inhibition capacity of TMZ-treated GBM cells. Additionally, actinomycin D reduced PD-L1 expression in GBM cells after TMZ challenge, indicating that PD-L1 induction occurred at transcriptional level. The immunoblotting results demonstrated that STAT3 signaling was involved in TMZ-mediated PD-L1 induction, and attenuated expression of PD-L1 was observed using STAT3 inhibitor VI or STAT3 shRNA. Finally, the animal study showed that combination of TMZ and PD-1 antibody therapy strongly inhibited tumor growth and achieved the improved survival rate of GBM mice. Accordingly, this study revealed the classical chemotherapy drug TMZ promoted GBM cells immune escape, even TMZ combine with PD-1 antibody treatment not further improve survival ratio of recurrent GBM patients compared with traditional therapy methods, while our animal study provided evidence that combination of TMZ and PD-1 antibody was a promising way to treat GBM, these contradictory results indicate improving the PD-1 antibody delivery efficiency can exert strong combinational therapy outcomes.

Dataset Information

PD-1 deficiency promotes TFH cells expansion in ITV-immunized mice by upregulating cytokines secretion.

Background

Methods

Results

Conclusions

Publications

PD-1 deficiency promotes TFH cells expansion in ITV-immunized mice by upregulating cytokines secretion.

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