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Published on: May 18, 2016
PD-1+ CD4 T cell immune response is mediated by HIF-1α/NFATc1 pathway after P. yoelii infection
Haixia Wei1,2, Anqi Xie2, Jiajie Li2
1Department of Infectious Diseases, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
Abstract:
The morbidity and mortality of malaria are still high. Programmed cell death-1(PD-1) is an important co-inhibitory factor and CD8 T cells with PD-1 were reported to be exhausted cells. It remains unknown what the role of CD4 T cells expressing PD-1 is and what the upstream regulating molecules of PD-1 in CD4 T cells are. The C57BL/6 mice were injected with Plasmodium yoelii (P. yoelii) in this study. Expressions of PD-1, activation markers, and cytokines were tested. The differentially expressed genes between PD-1+/- CD4 T cells were detected by microarray sequencing. Western blot, chromatin immunoprecipitation (ChIP), siRNA, hypoxia inducible factor-1α (HIF-1α) inducer and inhibitor were used to explore PD-1's upstream molecules, respectively. The proportions of PD-1+ CD4 T cells increased post P. yoelii infection. PD-1+ CD4 T cells expressed more activated surface markers and could produce more cytokines. Nuclear factor of activated T cells 1 (NFATc1) was found to be a key transcription factor to induce PD-1 expression after infection. Both the inducer and the inhibitor of HIF-1α could change the expressions of NFATc1 and PD-1 in vivo and in vitro, respectively. Taken together, P. yoelii infection induced NFATc1 expression by HIF-1α. The highly expressed NFATc1 entered the nucleus and initiated PD-1 expression. PD-1+ CD4 T cells appeared to be more activated and could secrete more cytokines to regulate the host's immune responses against malaria.
Insights
Malaria infection increases Programmed cell death-1 (PD-1) expressing CD4 T cells. Hypoxia inducible factor-1α (HIF-1α) induces NFATc1, which drives PD-1 expression, enhancing immune responses.
Area of Science:
- Immunology
- Infectious Diseases
- Molecular Biology
Background:
- Malaria remains a significant global health challenge with high morbidity and mortality.
- Programmed cell death-1 (PD-1) is a known co-inhibitory factor, typically associated with exhausted CD8 T cells.
- The specific role of PD-1 in CD4 T cells during malaria and its upstream regulators are not well understood.
Purpose of the Study:
- To investigate the function of CD4 T cells expressing PD-1 during Plasmodium yoelii infection.
- To identify the upstream molecules regulating PD-1 expression in CD4 T cells in this context.
- To elucidate the molecular mechanisms linking malaria infection to PD-1 expression on CD4 T cells.
Main Methods:
- C57BL/6 mice were infected with Plasmodium yoelii.
- Flow cytometry and gene expression analysis (microarray) were used to assess PD-1, activation markers, and cytokine production.
- Western blot, chromatin immunoprecipitation (ChIP), siRNA, and pharmacological modulators of hypoxia inducible factor-1α (HIF-1α) were employed to study PD-1 regulation.
Main Results:
- Plasmodium yoelii infection led to an increase in PD-1 expressing CD4 T cells.
- PD-1+ CD4 T cells exhibited enhanced expression of activation markers and produced higher levels of cytokines.
- Nuclear factor of activated T cells 1 (NFATc1) was identified as a key transcription factor for PD-1 induction.
- HIF-1α was found to regulate NFATc1 and PD-1 expression both in vivo and in vitro.
Conclusions:
- Plasmodium yoelii infection induces NFATc1 expression via HIF-1α in CD4 T cells.
- NFATc1 activation leads to increased nuclear translocation and subsequent PD-1 expression.
- PD-1+ CD4 T cells are characterized by heightened activation and cytokine production, potentially modulating host immune responses against malaria.
