Cited by 273T-cell and B-cell ImmunologyPsoriasis: Treatment and PathogenesisCancer Immunotherapy and Biomarkers

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CD3(+)CD4(-)CD8(-) (Double-negative) T cells in inflammation, immune disorders and cancer

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Wu, Zhiheng, Zheng, Yu, Sheng, Jin, Han, Yicheng, Yang, Yanyan, Pan, Hongming, Yao, Junlin·2022·Frontiers in Immunology

DOI 10.3389/fimmu.2022.816005PMC PMC8866817

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Abstract

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.

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Figure 1 Schematic diagram of DN T cell origin and distribution. Progenitor cells from the bone marrow colonize the corticomedullary junction of the thymus and generate the T cell lineage. In the DN3 stage, generally, high TCR strength makes TCRγδ+ DN thymocytes remain “double-negative”, whereas low TCR strength induces DN thymocytes with pre-TCRs to follow the αβ lineage fate. A small number of DP thymocytes differentiate into two distinct mature DN thymocyte subsets rather than entering the late SP stage: DN thymocytes selected by very strong TCR-MHC interactions preferentially migrate to the intestine where they re-express CD8α and are sequestered as CD8αα+ intraepithelial lymphocytes, while DN thymocytes selected by very weak TCR-MHC interactions become precursors to peripheral TCRαβ+ DN T cells. In peripheral circulation, CD4+/CD8+ T cells can also convert into DN T cells by downregulating CD4/CD8 expression. Peripheral DN T cells are localized in various organs in mice and humans. αβ, alpha and beta; Ag, antigen; DN, double-negative; DP, double-positive; γδ, gamma and delta; ISP, immature single-positive; MHC, major histocompatibility complex; SP, single-positive; TCR, T cell receptor.CC BY · PubMed Central

Figure 2 DN T cells participate in both innate and adaptive immunity. Based on Ag-TCR-specific recognition, DN T cells can inhibit or eliminate adaptive immune cells, suppressing diseases caused by immune responses. DN T cells can also secrete various cytokines to mediate innate immune responses. Ag, antigen; APC, antigen presenting cell; CXCL, chemokine ligand; DN, double-negative; IFN-γ, interferon-γ; IL, interleukin; M. tuberculosis, Mycobacterium tuberculosis; TCR, T cell receptor; TNF, tumor necrosis factor.CC BY · PubMed Central

Figure 3 Cell surface molecules or cytokines expressed by DN TILs show debatable antitumor or tumor-promoting activity during tumor development. DN, double-negative; TIL, tumor-infiltrating lymphocyte.CC BY · PubMed Central

Figure 4 Mechanisms of DN T cells in cancer treatment. (A) The killing effect of DN T cells toward AML cells can be perforin/granzyme B-dependent; IFN-γ enhances the effect of NKG2D and DNAM-1 in the DN T cell-mediated inhibition of AML cells. (B) NKG2D, DNAM-1 and soluble TRAIL participate in DN T cell-mediated lysis of NSCLC cells. (C) DN T cells eliminate pancreatic tumor cells through the Fas/FasL pathway. AML, acute myeloid leukemia; DN, double-negative; DNAM-1, DNAX accessory molecule-1; DNAM-1L, DNAX accessory molecule-1 ligand; FADD, Fas-associating protein with a novel death domain; FasL, Fas ligand; IFN-γ, interferon-γ; IFN-R, interferon receptor; NKG2D, natural-killer group 2, member D; NKG2DL, natural-killer group 2, member D ligand; NSCLC, non-small-cell lung cancer; TNF, tumor necrosis factor; TNF-R, tumor necrosis factor receptor; TRAIL, TNF-related apoptosis-inducing ligand; TRAIL-R, TNF-related apoptosis-inducing ligand receptor.CC BY · PubMed Central

Figure 5 The summary of multifunctional DN T cells in inflammation, immune disorders and cancer. DN T cells exert both regulatory and helper-like functions under different conditions and can exert antitumor activity in cancer treatment. DN, double-negative.CC BY · PubMed Central

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Authors: Wu, Z., Zheng, Y., Sheng, J., Han, Y., Yang, Y., Pan, H., & Yao, J.
Affiliations: Sir Run Run Shaw Hospital (CN)
Corresponding author: Pan, Hongming
Yao, Junlin
ORCID: Wu, Zhiheng
Han, Yicheng
Yang, Yanyan
Pan, Hongming
Yao, Junlin
Venue: Frontiers in Immunology
Publisher: Frontiers Media SA
Published: 2022-02-10
Volume: 13
Pages: 816005-816005
ISSN: 1664-3224 (ISSN-L)
DOI: 10.3389/fimmu.2022.816005
PMC: PMC8866817
OpenAlex: W4211100870
Cited by: 265
References: 116
Citations by year: 2026: 38 · 2025: 90 · 2024: 75 · 2023: 47 · 2022: 14
FWCI: 6.14
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (vor)
Locations: Frontiers in Immunology (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders: National Natural Science Foundation of China (81803070, 81702809)
Natural Science Foundation of Zhejiang Province (LSY19H160006)
Topics: Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Keywords: double-negative T cells, CD3+CD4-CD8- T cells, regulatory T cells, graft-versus-host disease, autoimmune disease, inflammation, viral infection, tumor-infiltrating lymphocytes, T cell heterogeneity
MeSH terms: Autoimmune Diseases, Graft vs Host Disease, Humans, Inflammation, Neoplasms, CD8 Antigens, CD8-Positive T-Lymphocytes

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CD3(+)CD4(-)CD8(-) (Double-negative) T cells in inflammation, immune disorders and cancer

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