CD4⁺ Cytotoxic T Lymphocytes in Cancer Immunity and Immunotherapy

Abstract

CD4+ T cells have the ability to differentiate into relatively specialized effector subsets after exposure to innate immune signals. The remarkable plasticity of CD4+ T cells is required to achieve immune responses in different tissues and against various pathogens. Numerous studies have shown that CD4+ T cells can play direct and indispensable roles in protective immunity by killing infected or transformed cells. Although the lineage decision of commitment to the CD4+ or CD8+ cell lineage is once thought to be inflexible, the identification of antigen‐experienced CD4+ T cells with cytotoxic activity suggests the existence of unexpected plasticity for these cells. The recognition of CD4+ cytotoxic T lymphocytes (CTLs) and the mechanisms driving the differentiation of this particular cell subset create opportunities to explore the roles of these effector cells in protective immunity and immune‐related pathology. CD4+ CTLs are proven to play a protective role in antiviral immunity. Here, the latest investigations on the phenotypic and functional features of CD4+ CTLs and their roles in antitumor immunity and immunotherapy are briefly reviewed.

Unraveling the causal role of immune cells in gastrointestinal tract cancers: insights from a Mendelian randomization study

“…Additionally, in secondary lymphoid organs, CD4+ T cells amplify the intensity and quality of B cell and Cytotoxic T lymphocytes (CTLs) responses. Antigen-specific interaction with CD4+ T cells enables dendritic cells (DCs) to optimize antigen presentation and deliver specific cytokine and co-stimulatory signals to CD8+ T cells, facilitating their clonal expansion and differentiation into effector or memory T cells ( 40 , 42 ). CD4+ T cells assist in initiating the gene expression program of CD8+ T cells, which enhances CTL function through various molecular mechanisms, enabling them to overcome obstacles commonly encountered in anticancer immunity ( 43 ).…”

Prognostic Value of Platelet Distribution Width to Lymphocyte Ratio in Patients with Hepatocellular Carcinoma Following Hepatectomy

“…Platelets were not always considered to be a single prognostic determinant, and ratios of biochemical tests, as well as formulas including platelet count, were tested as potential predictors of prognosis in patients with HCC. Lymphocytes have been shown to play an important role in cancer immune monitoring and the prevention of malignant tumor development [21]. A pro-in ammatory state can lead to impaired cell-mediated immunity and the impaired response of T lymphocytes induced by cytokines [22].…”

CTLs heterogeneity and plasticity: implications for cancer immunotherapy

“…NKG2D serves as a key activating receptor expressed in NK cells, and it is thought that CD4+ T cells expressing NKG2D have a putative cytotoxic function independent of the TCR-MHC pathway [ 48 ]. Researchers initially identified NKG2D-expressing CD4+ CTLs in B-CLLs [ 44 , 55 ]. CD4+NKG2D+ T cells are also thought to be cytotoxic cells and have been shown to be involved in rheumatoid arthritis (RA), Wegener’s granulomatosis (WG) and multiple sclerosis (MS), among other human autoimmune diseases [ 49 – 52 , 56 ].…”

“…According to the current studies, the differentiation process of CD4+ CTLs may involve three pathways (Fig. 2 ): (I) dependence on TCR signaling as the initiating event pathway, (II) signaling through the receptor CRTAM as the initiating event pathway, and (III) epigenetic regulatory modification pathway [ 5 , 55 , 59 , 74 ].

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“…Under appropriate stimulation (including TCR stimulation and IL-2/IL-15/type I IFN/IFN-γ), CD4+ Th cells can downregulate ThPOK for further differentiation into CD4+ CTLs [ 52 , 55 , 56 , 73 , 75 ]. The downregulation of THPOK is regulated by the RUNX3-THPOK silencing axis [ 59 ], which results in the upregulation of cytotoxicity-associated genes (e.g., Eomes, Ifng, GzmB and Prf1) [ 76 ].…”