γδ T cell exhaustion: Opportunities for intervention

Abstract

T lymphocytes are the key protective contributors in chronic infection and tumor, but experience exhaustion by persistent antigen stimulation. As an unconventional lineage of T cells, γδ T cells can rapidly response to varied infectious and tumor challenges in a non-MHC-restricted manner and play key roles in immune surveillance via pleiotropic effector functions, showing promising as candidates for cellular tumor immunotherapy. Activated γδ T cells can also acquire exhaustion signature with elevated expression of immune checkpoints, such as PD-1, decreased cytokine production, and functional impairment. However, the exhaustion features of γδ T cells are distinct from conventional αβ T cells. Here, we review the researches regarding the characteristics, heterogeneity, and mechanisms of γδ T cell exhaustion. These studies provide insights into the combined strategies to overcome the exhaustion of γδ T cells and enhance antitumor immunity.

Vγ9Vδ2 T-cell immunotherapy in blood cancers: ready for prime time?

“…gd T cells are equipped with a T-cell Receptor (TCR) composed of a g-chain (TRG) and a d-chain (TRD). The genes encoding TRG and TRD undergo somatic DNA recombination of variable (V), diversity (D, only in TRD) and joining (J) elements during gd T cell maturation in the thymus (1). gd TCR and ab TCR are structurally similar and associated with the same subunits of the CD3 complex which, however, are arranged differently and characterized by unique glycosylation patterns and other minor peculiarities (2, 3).…”

“…The genes encoding TRG and TRD undergo somatic DNA recombination of variable (V), diversity (D, only in TRD) and joining (J) elements during γδ T cell maturation in the thymus ( 1 ). γδ TCR and αβ TCR are structurally similar and associated with the same subunits of the CD3 complex which, however, are arranged differently and characterized by unique glycosylation patterns and other minor peculiarities ( 2 , 3 ). One major difference are the antigens recognized by αβ and γδ T cells and the modality of antigen recognition which is not dependent on the major histocompatibility complex (MHC) in γδ T cells ( 2 , 4 ).…”

“…γδ TCR and αβ TCR are structurally similar and associated with the same subunits of the CD3 complex which, however, are arranged differently and characterized by unique glycosylation patterns and other minor peculiarities ( 2 , 3 ). One major difference are the antigens recognized by αβ and γδ T cells and the modality of antigen recognition which is not dependent on the major histocompatibility complex (MHC) in γδ T cells ( 2 , 4 ). This feature is particularly exciting from the perspective of using γδ T cells as a source for adoptive cell transfer (ACT) or chimeric antigen receptor (CAR)-T cells because MHC-independency reduces the risk of graft-versus-host disease (GvHD) and helps the development of “off-the shelf” cellular products ( 5 ).…”

“…Human γδ T cells can be divided in three main subsets: Vδ1 + cells, Vδ2 + cells and Vδ3 + cells ( 2 ). Vδ2 + T cells are the predominant γδ T-cell population in the PB of adult humans ( 9 , 10 ).…”

Exhausted T cells hijacking the cancer-immunity cycle: Assets and liabilities

“…The predominant T cell type in the body is ab T cells (here referred to simply as T cells), and these express ab TCRs consisting of an aand a b subunit, while gd T cells express TCRs consisting of a gand a d subunit (21). Studies provides insights in the acquirement of an exhaustion signature by gd T cell, which has been extensively reviewed by Chen et al (22). Furthermore, it has been reported that gd T cells can have immunosuppressive functions, imposing immune exhaustion of antitumor ab T cells through PD-1/PD-L1 signaling (23).…”