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Nuclear factor of activated T cells 1 （NFAT1）， as a key transcription factor regulating T cell function， may participate in the pathogenesis of malaria by mediating the T cell exhaustion. This study aims to investigate the regulatory role of NFAT1 in the progression of Plasmodium berghei ANKA infection. By inhibiting NFAT1 activity and evaluating its effects on the expression of immune checkpoint molecules—T cell immunoglobulin and mucin domain-containing protein 3 （Tim-3）， cytotoxic T lymphocyte-associated antigen-4 （CTLA-4）， and programmed cell death-1 （PD-1）—in peripheral blood and spleen of Plasmodium-infected mice， this study further explore the potential therapeutic value of targeting NFAT1 for malaria treatment. Firstly， a C57BL/6 mouse infection model was established， serum lactate levels and peripheral blood NFAT1 protein expression （Western blot） were dynamically monitored at different time points （day 0， 4 and 7）. Flow cytometry was used to detect the expression levels of Tim-3， PD-1， and CTLA-4 on CD8+ T cells and NK cells in peripheral blood and spleen at different time points （day 0， 4， 6 and 8）. An intervention model was subsequently constructed， followed by sample collection at 48 hours post-intervention for immunophenotypic analysis. The results indicated that the serum lactate level in the infection group was significantly higher than that in the control group at the 4th （P<0.01） and the 7th （P<0.001）. The expression of NFAT1 protein was significantly upregulated at 7 days after infection （P<0.01）. Flow cytometry analysis showed that the proportions of Tim-3+， CTLA-4+， and PD-1+ subsets of CD8+ T cells/NK cells in the spleen and peripheral blood of mice were significantly increased at 6-8 days after infection （P<0.01）. After NFAT1 inhibitor intervention， the proportion of Tim-3+ CD8+ T/NK cells in the peripheral blood was significantly decreased （P<0.01）， and the proportions of CTLA-4+， Tim-3+ CD8+ T cells and Tim-3+， PD-1+ NK cells in the spleen were significantly reduced （P<0.01）. Notably， the proportion of CTLA-4+ NK cells in the peripheral blood was abnormally elevated after inhibitor treatment （P<0.001）.In conclusion， NFAT1 inhibition can partially down-regulate the expression of immune checkpoint molecules in CD8+ T/NK cells， but it is accompanied by the compensatory overexpression of CTLA-4 in NK cells， which may weaken its therapeutic effect. The research suggests that NFAT1-targeted therapy needs to be optimized in combination with the dynamic regulation mechanism of immune checkpoints， providing a new research direction for malaria immunotherapy strategies.
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| 科 Family | 属数 Number of genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) | 属 Genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) |
|---|---|---|---|---|---|---|
| 鹅膏菌科Amanitaceae | 2 | 11 | 5.26 | 鹅膏菌属 Amanita | 10 | 4.78 |
| 小菇科 Mycenaceae | 2 | 12 | 5.74 | 丝盖伞属 Inocybe | 5 | 2.39 |
| 多孔菌科 Polyporaceae | 8 | 14 | 6.70 | 蜡蘑属 Laccaria | 5 | 2.39 |
| 红菇科 Russulaceae | 3 | 23 | 11.00 | 小皮伞属 Marasmius | 6 | 2.87 |
| 小菇属 Mycena | 11 | 5.26 | ||||
| 光柄菇属 Pluteus | 5 | 2.39 | ||||
| 红菇属 Russula | 17 | 8.13 | ||||
| 栓菌属 Trametes | 5 | 2.39 |
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