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Review
. 2024 Jun 19;22(1):337.
doi: 10.1186/s12964-024-01714-7.

The role of KLRG1: a novel biomarker and new therapeutic target

Yakun Zhang #  1   2 , Shuang Chen #  2 , Xinyi Tang  1   2 , Yu Peng  2 , Tingting Jiang  2 , Xiaomei Zhang  2 , Jun Li  2 , Yao Liu  3 , Zailin Yang  4
Affiliations
Review

The role of KLRG1: a novel biomarker and new therapeutic target

Yakun Zhang et al. Cell Commun Signal. .

Abstract

Killer cell lectin-like receptor G1 (KLRG1) is an immune checkpoint receptor expressed predominantly in NK and T-cell subsets that downregulates the activation and proliferation of immune cells and participates in cell-mediated immune responses. Accumulating evidence has demonstrated the importance of KLRG1 as a noteworthy disease marker and therapeutic target that can influence disease onset, progression, and prognosis. Blocking KLRG1 has been shown to effectively mitigate the effects of downregulation in various mouse tumor models, including solid tumors and hematologic malignancies. However, KLRG1 inhibitors have not yet been approved for human use, and the understanding of KLRG1 expression and its mechanism of action in various diseases remains incomplete. In this review, we explore alterations in the distribution, structure, and signaling pathways of KLRG1 in immune cells and summarize its expression patterns and roles in the development and progression of autoimmune diseases, infectious diseases, and cancers. Additionally, we discuss the potential applications of KLRG1 as a tool for tumor immunotherapy.

Keywords: Biomarker; Immune checkpoint proteins; KLRG1; Therapeutic target; Tumor immunotherapy.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
KLRG1 signaling pathway. KLRG1 expressed on the surfaces of T-cells interacts with cadherin ligands expressed on the surfaces of cancer cells or APCs, promoting the phosphorylation of the ITIM intracellular structural domain, followed by the recruitment of the tyrosine-protein phosphatases SHIP-1 and SHP-2. In contrast to PI3K, SHIP-1 and SHP-2 inhibit AKT phosphorylation by degrading PIP3 to PIP2, thereby attenuating the activation of the mTOR pathway, leading to reduced T-cell effector function and proliferative dysfunction. In HCV-infected CD4+ T-cells, an increase in KLRG1 expression can inhibit AKT phosphorylation, thereby activating the transcription factor FOXO and increasing expression of the cell cycle inhibitor p27kip1 or directly activating p16ink4a to inhibit T-cell cycle progression. In NK cells, in addition to affecting the AKT pathway, KLRG1 can also be internalized after binding cadherin ligands, after which it binds directly to AMPK and prevents AMPK dephosphorylation by the protein phosphatase PP2C, which amplifies the activity of AMPK and leads to loss of NK cell function. The figure was created at BioRender.com
See this image and copyright information in PMC

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