CD3CD4CD8 (Double-Negative) T Cells in Inflammation, Immune Disorders and Cancer

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2022 Feb 28

PMID 35222392

Authors

Zhiheng Wu

Yu Zheng

Jin Sheng

Yicheng Han

Yanyan Yang

Hongming Pan

Junlin Yao

Affiliations

Soon will be listed here.

Abstract

The crucial role of CD4 and CD8 T cells in shaping and controlling immune responses during immune disease and cancer development has been well established and used to achieve marked clinical benefits. CD3CD4CD8 double-negative (DN) T cells, although constituting a rare subset of peripheral T cells, are gaining interest for their roles in inflammation, immune disease and cancer. Herein, we comprehensively review the origin, distribution and functions of this unique T cell subgroup. First, we focused on characterizing multifunctional DN T cells in various immune responses. DN regulatory T cells have the capacity to prevent graft-versus-host disease and have therapeutic value for autoimmune disease. T helper-like DN T cells protect against or promote inflammation and virus infection depending on the specific settings and promote certain autoimmune disease. Notably, we clarified the role of DN tumor-infiltrating lymphocytes and outlined the potential for malignant proliferation of DN T cells. Finally, we reviewed the recent advances in the applications of DN T cell-based therapy for cancer. In conclusion, a better understanding of the heterogeneity and functions of DN T cells may help to develop DN T cells as a potential therapeutic tool for inflammation, immune disorders and cancer.

Citing Articles

Thyroid Cancer-The Tumor Immune Microenvironment (TIME) over Time and Space.

Jaume J Cancers (Basel). 2025; 17(5).

PMID: 40075642 PMC: 11899416. DOI: 10.3390/cancers17050794.

Modulation of double-negative T cells by Huang-Lian-Jie-Du Decoction attenuates neuroinflammation in ischemic stroke: insights from single-cell transcriptomics.

Wang K, Sun Z, Shao Q, Wang Z, Zhang H, Li Y Front Immunol. 2025; 16:1537277.

PMID: 40018035 PMC: 11865039. DOI: 10.3389/fimmu.2025.1537277.

The effects of immune cell phenotypes and plasma metabolomes on diabetic foot ulcer: a Mendelian randomization study and mediation analysis.

Niu Z, Mao L, Han L, Niu J, Zhang X, Wei G Arch Dermatol Res. 2025; 317(1):460.

PMID: 39987406 DOI: 10.1007/s00403-025-03942-4.

CSTF2-impeded innate αβ T cell infiltration and activation exacerbate immune evasion of pancreatic cancer.

He X, Liu J, Zhou Y, Zhao S, Chen Z, Xu Z Cell Death Differ. 2025; .

PMID: 39972059 DOI: 10.1038/s41418-025-01464-0.

Causal effects of circulating immune cells on coronary atherosclerosis: Evidence from Mendelian randomization.

Yang X, Yu Y, Hu G, Bai S, Wu J, Guo C Medicine (Baltimore). 2025; 104(5):e41361.

PMID: 39889170 PMC: 11789883. DOI: 10.1097/MD.0000000000041361.

References

Bristeau-Leprince A, Mateo V, Lim A, Magerus-Chatinet A, Solary E, Fischer A . Human TCR alpha/beta+ CD4-CD8- double-negative T cells in patients with autoimmune lymphoproliferative syndrome express restricted Vbeta TCR diversity and are clonally related to CD8+ T cells. J Immunol. 2008; 181(1):440-8. DOI: 10.4049/jimmunol.181.1.440. View

Locksley R, Reiner S, Hatam F, Littman D, Killeen N . Helper T cells without CD4: control of leishmaniasis in CD4-deficient mice. Science. 1993; 261(5127):1448-51. DOI: 10.1126/science.8367726. View

Tian D, Yang L, Wang S, Zhu Y, Shi W, Zhang C . Double negative T cells mediate Lag3-dependent antigen-specific protection in allergic asthma. Nat Commun. 2019; 10(1):4246. PMC: 6751182. DOI: 10.1038/s41467-019-12243-0. View

Li H, Adamopoulos I, Moulton V, Stillman I, Herbert Z, Moon J . Systemic lupus erythematosus favors the generation of IL-17 producing double negative T cells. Nat Commun. 2020; 11(1):2859. PMC: 7275084. DOI: 10.1038/s41467-020-16636-4. View

Alunno A, Bistoni O, Bartoloni E, Caterbi S, Bigerna B, Tabarrini A . IL-17-producing CD4-CD8- T cells are expanded in the peripheral blood, infiltrate salivary glands and are resistant to corticosteroids in patients with primary Sjogren's syndrome. Ann Rheum Dis. 2012; 72(2):286-92. DOI: 10.1136/annrheumdis-2012-201511. View

Bernardo I, Mancebo E, Aguilo I, Anel A, Allende L, Guerra-Vales J . Phenotypic and functional evaluation of CD3+CD4-CD8- T cells in human CD8 immunodeficiency. Haematologica. 2011; 96(8):1195-203. PMC: 3148914. DOI: 10.3324/haematol.2011.041301. View

Huard B, Prigent P, Tournier M, Bruniquel D, Triebel F . CD4/major histocompatibility complex class II interaction analyzed with CD4- and lymphocyte activation gene-3 (LAG-3)-Ig fusion proteins. Eur J Immunol. 1995; 25(9):2718-21. DOI: 10.1002/eji.1830250949. View

Dudley E, Girardi M, Owen M, Hayday A . Alpha beta and gamma delta T cells can share a late common precursor. Curr Biol. 1995; 5(6):659-69. DOI: 10.1016/s0960-9822(95)00131-x. View

Sundaravaradan V, Saleem R, Micci L, Gasper M, Ortiz A, Else J . Multifunctional double-negative T cells in sooty mangabeys mediate T-helper functions irrespective of SIV infection. PLoS Pathog. 2013; 9(6):e1003441. PMC: 3694849. DOI: 10.1371/journal.ppat.1003441. View

10.

Zhang Z, Yang L, Young K, DuTemple B, Zhang L . Identification of a previously unknown antigen-specific regulatory T cell and its mechanism of suppression. Nat Med. 2000; 6(7):782-9. DOI: 10.1038/77513. View

11.

Pollyea D, Stevens B, Jones C, Winters A, Pei S, Minhajuddin M . Venetoclax with azacitidine disrupts energy metabolism and targets leukemia stem cells in patients with acute myeloid leukemia. Nat Med. 2018; 24(12):1859-1866. PMC: 7001730. DOI: 10.1038/s41591-018-0233-1. View

12.

Di Blasi D, Boldanova T, Mori L, Terracciano L, Heim M, De Libero G . Unique T-Cell Populations Define Immune-Inflamed Hepatocellular Carcinoma. Cell Mol Gastroenterol Hepatol. 2019; 9(2):195-218. PMC: 6957799. DOI: 10.1016/j.jcmgh.2019.08.004. View

13.

Martina M, Noel S, Saxena A, Bandapalle S, Majithia R, Jie C . Double-Negative αβ T Cells Are Early Responders to AKI and Are Found in Human Kidney. J Am Soc Nephrol. 2015; 27(4):1113-23. PMC: 4814175. DOI: 10.1681/ASN.2014121214. View

14.

Stankovic B, Bjorhovde H, Skarshaug R, Aamodt H, Frafjord A, Muller E . Immune Cell Composition in Human Non-small Cell Lung Cancer. Front Immunol. 2019; 9:3101. PMC: 6367276. DOI: 10.3389/fimmu.2018.03101. View

15.

Liu Z, Meng Q, Bartek Jr J, Poiret T, Persson O, Rane L . Tumor-infiltrating lymphocytes (TILs) from patients with glioma. Oncoimmunology. 2017; 6(2):e1252894. PMC: 5353900. DOI: 10.1080/2162402X.2016.1252894. View

16.

Paul S, Shilpi , Lal G . Role of gamma-delta (γδ) T cells in autoimmunity. J Leukoc Biol. 2014; 97(2):259-71. DOI: 10.1189/jlb.3RU0914-443R. View

17.

Zhao X, Sun G, Sun X, Tian D, Liu K, Liu T . A novel differentiation pathway from CD4⁺ T cells to CD4⁻ T cells for maintaining immune system homeostasis. Cell Death Dis. 2016; 7:e2193. PMC: 4855662. DOI: 10.1038/cddis.2016.83. View

18.

Wang L, Yang J, Kabaleeswaran V, Rice A, Cruz A, Park A . The Fas-FADD death domain complex structure reveals the basis of DISC assembly and disease mutations. Nat Struct Mol Biol. 2010; 17(11):1324-9. PMC: 2988912. DOI: 10.1038/nsmb.1920. View

19.

Duncan B, Nazarov-Stoica C, Surls J, Kehl M, Bona C, Casares S . Double negative (CD3+ 4- 8-) TCR alphabeta splenic cells from young NOD mice provide long-lasting protection against type 1 diabetes. PLoS One. 2010; 5(7):e11427. PMC: 2896421. DOI: 10.1371/journal.pone.0011427. View

20.

Lee J, Khan D, Hurren R, Xu M, Na Y, Kang H . Venetoclax enhances T cell-mediated antileukemic activity by increasing ROS production. Blood. 2021; 138(3):234-245. PMC: 8310428. DOI: 10.1182/blood.2020009081. View