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1.400038 重庆,陆军军医大学(第三军医大学):基础医学院免疫学教研室
2.400038 重庆,陆军军医大学(第三军医大学):药学与检验医学系药物分析学教研室
[王莉, E-mail: liwang118@tmmu.edu.cnWANG Li, E-mail: liwang118@tmmu.edu.cn
收稿:2023-12-11,
修回:2024-01-10,
纸质出版:2024-04-30
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杨数数, 刘东, 黎婕, 等. 雌性和雄性非肥胖糖尿病小鼠中CD8+ T细胞分化亚群差异研究[J]. 陆军军医大学学报, 2024,46(8):837-848.
Shushu YANG, Dong LIU, Jie LI, et al. Characterization of CD8+ T cell subsets in male and female non-obese diabetic mice[J]. Journal of Army Medical University, 2024, 46(8): 837-848.
杨数数, 刘东, 黎婕, 等. 雌性和雄性非肥胖糖尿病小鼠中CD8+ T细胞分化亚群差异研究[J]. 陆军军医大学学报, 2024,46(8):837-848. DOI: 10.16016/j.2097-0927.202312058.
Shushu YANG, Dong LIU, Jie LI, et al. Characterization of CD8+ T cell subsets in male and female non-obese diabetic mice[J]. Journal of Army Medical University, 2024, 46(8): 837-848. DOI: 10.16016/j.2097-0927.202312058.
目的
2
以雌性和雄性非肥胖糖尿病(nonobese diabetic
NOD)小鼠以及健康对照癌症研究所(institute for cancer research
ICR)小鼠为研究对象,比较分析初始、效应、记忆、耗竭以及调节性CD8
+
T细胞分化亚群差异,探讨1型糖尿病(type 1 diabetes
T1D)背景下的性别因素对CD8
+
T细胞分化命运的影响。
方法
2
采用流式细胞术检测雌雄NOD小鼠脾脏、胰腺引流淋巴结(pancreatic draining lymph nodes
pLN)、胰腺浸润淋巴细胞(pancreas-infiltrating lymphocytes
PIL)、初始T细胞(na?ve T cells
T
N
)、中枢记忆T细胞(central memory T cells
T
CM
)、效应T细胞(effector T cells
T
EFF
)、效应前体样T细胞(effector precursor T cells
T
EP
)、耗竭T细胞(exhausted T cells
T
EX
)、耗竭前体T细胞(precursor exhausted T cells
T
PEX
)以及调节性T细胞(regulatory T cells
Tregs)等CD8
+
T细胞分化亚群的频率和表型差异。
结果
2
与雄性NOD小鼠比较,雌性NOD小鼠pLN及PIL中IFN-γ
+
、CD107a
+
和CCL5
+
CD8
+
T
EFF
频率显著升高(
P
<
0.01
P
<
0.05
P
<
0.05),同时脾脏中CD8
+
T
N
、CD8
+
T
CM
、CD8
+
T
EX
、CD8
+
T
PEX
和CD122
+
CD8
+
Tregs亚群的频率均显著降低(
P
<
0.01
P
<
0.01
P
<
0.01
P
<
0.01
P
<
0.001);而雌性和雄性ICR小鼠体内除CD122
+
CD8
+
Tregs差异变化与NOD小鼠一致(
P
<
0.05),其余上述各CD8
+
T细胞分化亚群无显著差异。
结论
2
雄激素可能通过抑制记忆T细胞向效应T细胞分化,同时促进效应T细胞功能耗竭,导致雌雄发病率差异。
Objective
2
To compare and analyze the differences in CD8
+
naive
effector
memory
exhausted and regulatory T cells in order to investigate the impact of gender on the differentiation fate of CD8
+
T cells in the context of type 1 diabetes (T1D) based on female and male non-obese diabetic (NOD) mice and healthy Institute for Cancer Research (ICR) mice.
Methods
2
The frequencies and phenotypes of CD8
+
T cell differentiation subsets including naive T cells (T
N
)
central memory T cells (T
CM
)
effector T cells (T
EFF
)
effector precursor T cells (T
EP
)
exhausted T cells (T
EX
)
precursor exhausted T cells (T
PEX
) and regulatory T cells (Tregs) in the spleen
pancreatic draining lymph nodes (pLN) and pancreas infiltrating lymphocytes (PIL) of male and female NOD mice were detected by flow cytometry.
Results
2
The frequencies of IFN-γ
+
CD107a
+
and CCL5
+
CD8
+
T
EFF
in pLN and PIL of female NOD mice were significantly higher than those of
male NOD mice. However
the frequencies of CD8
+
T
N
CD8
+
T
CM
CD8
+
T
EX
CD8
+
T
PEX
and CD122
+
CD8
+
Tregs subsets in the spleen were significantly decreased. While there were no significant differences in the above CD8
+
T cell subsets except CD8
+
Tregs between female and male ICR mice.
Conclusion
2
Androgen may inhibit the differentiation of memory T cells into effector T cells and promote the exhaustion of effector T cells
leading to the difference in morbidity between the male and female mice.
WENG J P, ZHOU Z G, GUO L X, et al . Incidence of type 1 diabetes in China, 2010-13: population based study[J ] . Br Med J, 2018, 360: j5295. DOI: 10.1136/bmj.j5295.
WENG J P, ZHOU Z G, GUO L X. Comment on Liu, et al. incidence of type 1 diabetes may be underestimated in the Chinese population: evidence from 21.7 million people between 2007 and 2017. diabetes care 2021;44: 2503-2509[J ] . Diabetes Care, 2022, 45(1): e12. DOI: 10.2337/dc21-1820 http://dx.doi.org/10.2337/dc21-1820 .
KLEIN S L, FLANAGAN K L. Sex differences in immune responses[J]. Nat Rev Immunol, 2016, 16(10): 626-638. DOI: 10.1038/nri.2016.90.
MOULTON V R. Sex hormones in acquired immunity and autoimmune disease[J]. Front Immunol, 2018, 9: 2279. DOI: 10.3389/fimmu.2018.02279.
VASANTHAKUMAR A, CHISANGA D, BLUME J, et al . Sex-specific adipose tissue imprinting of regulatory T cells[J ] . Nature, 2020, 579(7800): 581-585. DOI: 10.1038/s41586-020-2040-3.
SHEPHERD R, CHEUNG A S, PANG K, et al . Sexual dimorphism in innate immunity: the role of sex hormones and epigenetics[J ] . Front Immunol, 2020, 11: 604000. DOI: 10.3389/fimmu.2020.604000.
YOUNG E F, HESS P R, ARNOLD L W, et al . Islet lymphocyte subsets in male and female NOD mice are qualitatively similar but quantitatively distinct[J ] . Autoimmunity, 2009, 42(8): 678-691. DOI: 10.3109/08916930903213993.
KIKUTANI H, MAKINO S. The murine autoimmune diabetes model: nod and related strains[J]. Adv Immunol, 1992, 51: 285-322. DOI: 10.1016/s0065-2776(08)60490-3.
YURKOVETSKIY L, BURROWS M, KHAN A A, et al . Gender bias in autoimmunity is influenced by microbiota[J ] . Immunity, 2013, 39(2): 400-412. DOI: 10.1016/j.immuni.2013.08.013.
GEARTY S V, DÜNDAR F, ZUMBO P, et al . An autoimmune stem-like CD8 T cell population drives type 1 diabetes[J ] . Nature, 2022, 602(7895): 156-161. DOI: 10.1038/s41586-021-04248-x.
AKTAS E, KUCUKSEZER U C, BILGIC S, et al . Relationship between CD107a expression and cytotoxicactivity[J ] . Cell Immunol, 2009, 254(2): 149-154. DOI: 10.1016/j.cellimm.2008.08.007.
COHNEN A, CHIANG S C, STOJANOVIC A, et al . Surface CD107a/LAMP-1 protects natural killer cells from degranu lation-associated damage[J ] . Blood, 2013, 122(8): 1411-1418. DOI: 10.1182/blood-2012-07-441832.
XIONG H, CUI M T, KONG N, et al . Cytotoxic CD161-CD8 + TEMRA cells contribute to the pathogenesis of systemic lupuserythematosus[J ] . EBioMedicine, 2023, 90: 104507. DOI: 10.1016/j.ebiom.2023.104507..
HINRICHS A C, BLOKLAND S L M, LOPES A P, et al . Transcriptome analysis of CCR9+ T helper cells from primary sjögren's syndrome patients identifies CCL5 asa novel effector molecule[J ] . Front Immunol, 2021, 12: 702733. DOI: 10.3389/fimmu.2021.702733.
LEQUEUX A, NOMAN M Z, XIAO M, et al . Targeting HIF-1 alpha transcriptional activity drives cytotoxic immune effector cells into melanoma and improves combination immunotherapy[J ] . Oncogene, 2021, 40(28): 4725-4735. DOI: 10.1038/s41388-021-01846-x.
SPRENT J, ZHANG X, SUN S, et al . T-cell proliferation in vivo and the role of cytokines[J ] . Philos Trans R Soc Lond B Biol Sci, 2000, 355(1395): 317-322. DOI: 10.1098/rstb.2000.0568.
GATTINONI L, ZHONG X S, PALMER D C, et al . Wnt signaling arrest s effector T cell differentiation and generates CD8 + memory stem cells[J ] . Nat Med, 2009, 15(7): 808-813. DOI: 10.1038/nm.1982..
NAKAJIMA Y, CHAMOTO K, OURA T, et al . Critical role of the CD44 low CD62L low CD8 + T cell subset in restoring antitumor immunity in aged mice[J ] . Proc Natl Acad Sci U S A, 2021, 118(23): e2103730118. DOI: 10.1073/pnas.2103730118..
HASHIMOTO M, KAMPHORST A O, IM S J, et al . CD8 T cell exhaustion in chronic infection and cancer: opportunities for interventions[J ] . Annu Rev Med, 2018, 69: 301-318. DOI: 10.1146/annurev-med-012017-043208.
WU T Q, JI Y, MOSEMAN E A, et al . The TCF1-Bcl6 axis counteracts type Ⅰ interferon to repress exhaustion and maintain T cell stemness[J ] . Sci Immunol, 2016, 1(6): eaai8593. DOI: 10.1126/sciimmunol.aai8593.
MCLANE L M, ABDEL-HAKEEM M S, WHERRY E J. CD8 T cell exhaustion during chronic viral infection and cancer[J]. Annu Rev Immunol, 2019, 37: 457-495. DOI: 10.1146/annurev-immunol-041015-055318.
WEISSHAAR N, WU J X, MING Y N, et al . Rgs16 promotes antitumor CD8 + T cell exhaustion[J ] . Sci Immunol, 2022, 7(71): eabh1873. DOI: 10.1126/sciimmunol.abh1873..
DAI Z, ZHANG S, XIE Q, et al . Natural CD8 + CD122 + T cells are more potent in suppression of allograft rejection than CD4 + CD25 + regulatory T cells[J ] . Am J Transplant, 2014, 14(1): 39-48. DOI: 10.1111/ajt.12515..
ARNDT B, WITKOWSKI L, ELLWART J, et al . CD8 + CD122 + PD-1-effector cells promote the development of diabetes in NOD mice[J ] . J Leukoc Biol, 2015, 97(1): 111-120. DOI: 10.1189/jlb.3A0613-344RR..
WANG F D, CHENG F J, ZHENG F. Stem cell like memory T cells: a new paradigm in cancer immunotherapy[J]. Clin Immunol, 2022, 241: 109078. DOI: 10.1016/j.clim.2022.109078.
GATTINONI L, LUGLI E, JI Y, et al . A human memory T cell subset with stem cell-like properties[J ] . Nat Med, 2011, 17(10): 1290-1297. DOI: 10.1038/nm.2446.
SMERDON R A, PEAKMAN M, HUSSAIN M J, et al . Increase in simultaneous coexpression of naive and memory lymphocyte markers at diagnosis of IDDM[J ] . Diabetes, 1993, 42( 1): 127-133. DOI: 10.2337/diab.42.1.127.
ZHANG Y, JOE G, HEXNER E, et al . Host-reactive CD8 + memory stem cells in graft-versus-host disease[J ] . Nat Med, 2005, 11(12): 1299-1305. DOI: 10.1038/nm1326..
KWON H, SCHAFER J M, SONG N J, et al . Androgen conspires with the CD8 + T cell exhaustion program and contributes to sex bias in cancer[J ] . Sci Immunol, 2022, 7(73): eabq2630. DOI: 10.1126/sciimmunol.abq2630..
GUAN X N, POLESSO F, WANG C J, et al . Androgen receptor activity in T cells limits checkpoint blockade efficacy[J ] . Nature, 2022, 606(7915): 791-796. DOI: 10.1038/s41586-022-04522-6
ANSARI M J, SALAMA A D, CHITNIS T, et al . The programmed death-1 (PD-1) pathway regulates autoimmune diabetes in nonobese diabetic (NOD) mice[J ] . J Exp Med, 2003, 198(1): 63-69. DOI: 10.1084/jem.20022125.
傅昭粤, 沈娱汀, 李娟, 等. +15Gz重复暴露对小鼠CD4 + T淋巴细胞的影响[J ] . 空军军医大学学报, 2023, 44(1): 42-47. DOI: 10.13276/j.issn.2097-1656.2023.01.008.
FU Z Y, SHEN Y T, LI J, et al . Effects o f repeated +15Gz exposure on mouse CD4 + T lymphocytes[J ] . J Air Force Med Univ, 2023, 44(1): 42-47. DOI: 10.13276/j.issn.2097-1656.2023.01.008..
STOCKSB T, WILSON C S, MARSHALL A F, et al . Regulation of diabetogenic immunity by IL-15-activated regulatory CD8 T cells in type 1 diabetes[J ] . J Immunol, 2019, 203(1): 158-166. DOI: 10.4049/jimmunol.1800976.
LIU H Z, WANG Y S, ZENG Q H, et al . Suppression of allograft rejection by CD8 + CD122 + PD-1+ Tregs is dictated by their Fas ligand-initiated killing of effector T cells versus Fas-mediated own apoptosis[J ] . Oncotarget, 2017, 8(15): 24187-24195. DOI: 10.18632/oncotarget.15551..
SHIMOKAWA C, KATO T, TAKEUCHI T, et al . CD8 + regulatory T cells are critical in prevention of autoimmune-mediated diabetes[J ] . Nat Commun, 2020, 11(1): 1922. DOI: 10.1038/s41467-020-15857-x..
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