CD3+CD4-CD8- (Double-Negative) T Cells in Inflammation, Immune Disorders and Cancer

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. CD3⁺CD4^-CD8^- 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.

Keywords: cancer; double-negative T cell; helper function; immune disorders; immunoregulation; immunotherapy; inflammation; tumor microenvironment.

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.

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.

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.

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.

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.