Department of Pathogenic Biology, College of Basic Medical Sciences, Army Medical University (Third Military Medical University), Chongqing, China
LIU Taiping, E-mail: liutaiping@tmmu.edu.cn
Received:02 December 2025,
Revised:2026-01-07,
Accepted:07 January 2026,
Published:30 January 2026
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李航宇,高源利,范永铃,等.CD4+T细胞通过分泌IFN-γ促进伯氏疟原虫红内期感染虫荷的机制研究[J].陆军军医大学学报,2026,48(02):107-115.DOI:10.16016/j.2097-0927.202512008.
LI H Y,GAO Y L,FAN Y L,et al.CD4⁺T cells promote Plasmodium berghei blood-stage burden via IFN-γ secretion[J].J Army Med Univ,2026,48(02):107-115.DOI:10.16016/j.2097-0927.202512008.
李航宇,高源利,范永铃,等.CD4+T细胞通过分泌IFN-γ促进伯氏疟原虫红内期感染虫荷的机制研究[J].陆军军医大学学报,2026,48(02):107-115.DOI:10.16016/j.2097-0927.202512008. DOI:
LI H Y,GAO Y L,FAN Y L,et al.CD4⁺T cells promote Plasmodium berghei blood-stage burden via IFN-γ secretion[J].J Army Med Univ,2026,48(02):107-115.DOI:10.16016/j.2097-0927.202512008. DOI:
目的
2
探讨CD4⁺T细胞来源的IFN-γ在宿主抗伯氏疟原虫(
Plasmodium berghei
,
P. berghei
)红内期感染中的作用及机制。
方法
2
采用他莫昔芬诱导性条件敲除策略,构建仅在CD4⁺T细胞中缺失IFN-γ基因的小鼠模型(
Ifng
fl/fl
CD4-CreER
T2
)。而后经尾静脉感染表达萤光素酶的伯氏疟原虫ANKA株(
P.berghei
ANKA-luciferase),动态检测感染小鼠体内虫荷、存活率及疟原虫发育节律;流式细胞术检测脾脏髓系细胞亚群频率和数量;ELISA检测疟原虫特异性IgG和IgG2c抗体水平。
结果
2
CD4⁺T细胞特异性缺失IFN-γ会显著降低小鼠感染第5天原虫血症(
P
<
0.05),但不影响生存率,也不干扰伯氏疟原虫24 h的红内期发育周期。
Ifng
fl/fl
CD4-CreER
T2
感染小鼠血清疟原虫特异性抗体亚型IgG2c滴度减少(
P
<
0.01)、但总IgG滴度显著升高(
P
<
0.05)。中性粒细胞、单核细胞和巨噬细胞的频率和数量无统计学差异。
结论
2
伯氏疟原虫红内期感染进程中,CD4⁺T细胞分泌的IFN-γ可能通过促进疟原虫特异性IgG抗体向IgG2c类别转换,降低血清IgG水平,进而增强伯氏疟原虫红内期感染小鼠体内虫荷。
Objective
2
To investigate the role and mechanism of CD4⁺ T-cell-derived IFN-γ in host defense against blood-stage
Plasmodium berghei
(
P. berghei
) infection.
Methods
2
A tamoxifen-inducible conditional knockout strategy was performed to generate mice lacking IFN-γ specifically in CD4⁺T cells (
Ifng
fl/fl
CD4-CreER
T2
). Then after the mice were infected intravenously with luciferase-expressing
P. berghei
ANKA (
P. berghei
ANKA-luciferase) strain
parasite burden
survival
and intra-erythrocytic developmental rhythm were monitored dynamically. Flow cytometry and ELISA were carried out respectively to quantify the splenic myeloid subsets and the titers of
P. berghei
-specific IgG and IgG2c.
Results
2
CD4⁺T-cell-specific IFN-γ deficiency significantly reduced peripheral parasitemia on day 5 post-infection (
P
<
0.05)
showing no effect on survival or 24-hour intra-erythrocytic cycle of the parasite.
Ifng
fl/fl
CD4-CreER
T2
mice exhibited obviously decreased
P. berghei
-specific IgG2c (
P
<
0.01) but increased total IgG (
P
<
0.05). Frequencies and absolute numbers of neutrophils
monocytes
and macrophages remained unchanged.
Conclusion
2
During the process of
P. berghei
infection
IFN-γ secreted by CD4⁺T cells may decrease total serum IgG level by promoting class switching to IgG2c
and then enhance parasite burden after blood-stage
P. berghei
infection.
VENKATESAN P . WHO world malaria report 2024 [J]. Lancet Microbe , 2025 : 101073 . DOI: 10.1016/j.lanmic. 2025.101073 http://dx.doi.org/10.1016/j.lanmic.2025.101073 .
THERA M A , DOUMBO O K , COULIBALY D , et al . A field trial to assess a blood-stage malaria vaccine [J]. N Engl J Med , 2011 , 365 ( 11 ): 1004 - 1013 . DOI: 10.1056/NEJMoa 1008115 http://dx.doi.org/10.1056/NEJMoa1008115 .
HODGSON S H , CHOUDHARY P , ELIAS S C , et al . Combining viral vectored and protein-in-adjuvant vaccines against the blood-stage malaria antigen AMA1: report on a phase 1a clinical trial [J]. Mol Ther , 2014 , 22 ( 12 ): 2142 - 2154 . DOI: 10.1038/mt.2014.157 http://dx.doi.org/10.1038/mt.2014.157 .
SHEEHY S H , DUNCAN C J A , ELIAS S C , et al . ChAd63-MVA-vectored blood-stage malaria vaccines targeting MSP1 and AMA1: assessment of efficacy against mosquito bite challenge in humans [J]. Mol Ther , 2012 , 20 ( 12 ): 2355 - 2368 . DOI: 10.1038/mt.2012.223 http://dx.doi.org/10.1038/mt.2012.223 .
SÜSS G , EICHMANN K , KURY E , et al . Roles of CD4- and CD8-bearing T lymphocytes in the immune response to the erythrocytic stages of Plasmodium chabaudi [J]. Infect Immun , 1988 , 56 ( 12 ): 3081 - 3088 . DOI: 10.1128/iai.56.12.3081-3088.1988 http://dx.doi.org/10.1128/iai.56.12.3081-3088.1988 .
MEDING S J , LANGHORNE J . CD4 + T cells and B cells are necessary for the transfer of protective immunity to Plasmodium chabaudi chabaudi [J]. Eur J Immunol , 1991 , 21 ( 6 ): 1433 - 1438 . DOI: 10.1002/eji.1830210616 http://dx.doi.org/10.1002/eji.1830210616 .
PÉREZ-MAZLIAH D , NGUYEN M P , HOSKING C , et al . Follicular helper T cells are essential for the elimination of Plasmodium Infection [J]. EBioMedicine , 2017 , 24 : 216 - 230 . DOI: 10.1016/j.ebiom.2017.08.030 http://dx.doi.org/10.1016/j.ebiom.2017.08.030 .
ZHU J F , PAUL W E . CD4 T cells: fates, functions, and faults [J]. Blood , 2008 , 112 ( 5 ): 1557 - 1569 . DOI: 10.1182/blood-2008-05-078154 http://dx.doi.org/10.1182/blood-2008-05-078154 .
AGHAJANI K , KEERTHIVASAN S , YU Y , et al . Generation of CD4CreER(T²) transgenic mice to study development of peripheral CD4-T-cells [J]. Genesis , 2012 , 50 ( 12 ): 908 - 913 . DOI: 10.1002/dvg.22052 http://dx.doi.org/10.1002/dvg.22052 .
VAN DER HEYDE H C , PEPPER B , BATCHELDER J , et al . The time course of selected malarial infections in cytokine-deficient mice [J]. Exp Parasitol , 1997 , 85 ( 2 ): 206 - 213 . DOI: 10.1006/expr.1996.4132 http://dx.doi.org/10.1006/expr.1996.4132 .
SU Z , STEVENSON M M . Central role of endogenous gamma interferon in protective immunity against blood-stage Plasmodium chabaudi AS infection [J]. Infect Immun , 2000 , 68 ( 8 ): 4399 - 4406 . DOI: 10.1128/IAI.68.8.4399-4406.2000 http://dx.doi.org/10.1128/IAI.68.8.4399-4406.2000 .
AMANI V , VIGÁRIO A M , BELNOUE E , et al . Involvement of IFN-gamma receptor-medicated signaling in pathology and anti-malarial immunity induced by Plasmodium berghei infection [J]. Eur J Immunol , 2000 , 30 ( 6 ): 1646 - 1655 . DOI: 10.1002/1521-4141(200006)30: 61646: : AID-IMMU1646>3.0.CO;2-0 http://dx.doi.org/10.1002/1521-4141(200006)30:61646::AID-IMMU1646>3.0.CO;2-0 .
FAVRE N , RYFFEL B , BORDMANN G , et al . The course of Plasmodium chabaudi chabaudi infections in interferon-gamma receptor deficient mice [J]. Parasite Immunol , 1997 , 19 ( 8 ): 375 - 383 . DOI: 10.1046/j.1365-3024.1997.d01-227.x http://dx.doi.org/10.1046/j.1365-3024.1997.d01-227.x .
WAKI S , UEHARA S , KANBE K , et al . Interferon-gamma and the induction of protective IgG2a antibodies in non-lethal Plasmodium berghei infections of mice [J]. Parasite Immunol , 1995 , 17 ( 10 ): 503 - 508 . DOI: 10.1111/j.1365-3024.1995.tb00880.x http://dx.doi.org/10.1111/j.1365-3024.1995.tb00880.x .
DE JONG S E , VAN UNEN V , MANURUNG M D , et al . Systems analysis and controlled malaria infection in Europeans and Africans elucidate naturally acquired immunity [J]. Nat Immunol , 2021 , 22 ( 5 ): 654 - 665 . DOI: 10.1038/s41590-021-00911-7 http://dx.doi.org/10.1038/s41590-021-00911-7 .
MORDMÜLLER B , SURAT G , LAGLER H , et al . Sterile protection against human malaria by chemoattenuated PfSPZ vaccine [J]. Nature , 2017 , 542 ( 7642 ): 445 - 449 . DOI: 10.1038/nature21060 http://dx.doi.org/10.1038/nature21060 .
BUTLER N S , MOEBIUS J , PEWE L L , et al . Therapeutic blockade of PD-L1 and LAG-3 rapidly clears established blood-stage Plasmodium infection [J]. Nat Immunol , 2011 , 13 ( 2 ): 188 - 195 . DOI: 10.1038/ni.2180 http://dx.doi.org/10.1038/ni.2180 .
SCHRODER K , HERTZOG P J , RAVASI T , et al . Interferon-gamma: an overview of signals, mechanisms and functions [J]. J Leukoc Biol , 2004 , 75 ( 2 ): 163 - 189 . DOI: 10.1189/jlb.0603252 http://dx.doi.org/10.1189/jlb.0603252 .
BOSSIE A , VITETTA E S . IFN-gamma enhances secretion of IgG2a from IgG2a-committed LPS-stimulated murine B cells: implications for the role of IFN-gamma in class switching [J]. Cell Immunol , 1991 , 135 ( 1 ): 95 - 104 . DOI: 10.1016/0008-8749(91)90257-c http://dx.doi.org/10.1016/0008-8749(91)90257-c .
SNAPPER C M , PESCHEL C , PAUL W E . IFN-gamma stimulates IgG2a secretion by murine B cells stimulated with bacterial lipopolysaccharide [J]. J Immunol , 1988 , 140 ( 7 ): 2121 - 2127 .
MARTIN R M , BRADY J L , LEW A M . The need for IgG2c specific antiserum when isotyping antibodies from C57BL/6 and NOD mice [J]. J Immunol Methods , 1998 , 212 ( 2 ): 187 - 192 . DOI: 10.1016/s0022-1759(98)00015-5 http://dx.doi.org/10.1016/s0022-1759(98)00015-5 .
DREWRY L L , PEWE L L , HANCOX L S , et al . CD4 T cell-dependent and-independent roles for IFN-γ in blood-stage malaria [J]. J Immunol , 2023 , 210 ( 9 ): 1305 - 1313 . DOI: 10.4049/jimmunol.2200899 http://dx.doi.org/10.4049/jimmunol.2200899 .
VIDARSSON G , DEKKERS G , RISPENS T . IgG subclasses and allotypes: from structure to effector functions [J]. Front Immunol , 2014 , 5 : 520 . DOI: 10.3389/fimmu.2014.00520 http://dx.doi.org/10.3389/fimmu.2014.00520 .
PLAYOUST E , REMARK R , VIVIER E , et al . Germinal center-dependent and-independent immune responses of tumor-infiltrating B cells in human cancers [J]. Cell Mol Immunol , 2023 , 20 ( 9 ): 1040 - 1050 . DOI: 10.1038/s41423-023-01060-7 http://dx.doi.org/10.1038/s41423-023-01060-7 .
JARAMILLO M , GOWDA D C , RADZIOCH D , et al . Hemozoin increases IFN-gamma-inducible macrophage nitric oxide generation through extracellular signal-regulated kinase- and NF-kappa B-dependent pathways [J]. J Immunol , 2003 , 171 ( 8 ): 4243 - 4253 . DOI: 10.4049/jimmunol.171.8.4243 http://dx.doi.org/10.4049/jimmunol.171.8.4243 .
GAO Y L , CHEN S L , JIAO S M , et al . ATG5-regulated CCL2/MCP-1 production in myeloid cells selectively modulates anti-malarial CD4 + Th1 responses [J]. Autophagy , 2024 , 20 ( 6 ): 1398 - 1417 . DOI: 10.1080/15548627.2024.2319512 http://dx.doi.org/10.1080/15548627.2024.2319512 .
HOJO-SOUZA N S , DE AZEVEDO P O , DE CASTRO J T , et al . Contributions of IFN-γ and granulysin to the clearance of Plasmodium yoelii blood stage [J]. PLoS Pathog , 2020 , 16 ( 9 ): e1008840 . DOI: 10.1371/journal.ppat.1008840 http://dx.doi.org/10.1371/journal.ppat.1008840 .
VILLEGAS-MENDEZ A , GREIG R , SHAW T N , et al . IFN-γ-producing CD4 + T cells promote experimental cerebral malaria by modulating CD8 + T cell accumulation within the brain [J]. J Immunol , 2012 , 189 ( 2 ): 968 - 979 . DOI: 10.4049/jimmunol.1200688 http://dx.doi.org/10.4049/jimmunol.1200688 .
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