Fast‐acting γδ T‐cell subpopulation and protective immunity against infections

Abstract

T cells expressing γδ T cell antigen receptors (TCR) are a non-conventional T-cell population. 1-3 In humans and non-human primates (NHPs), there is a unique γδ T cell subpopulation expressing TCR heterodimer bearing Vγ2 and Vδ2 segments, termed Vγ2Vδ2 (also Vγ9Vδ2) T cells. 4 Studies carried out over several decades have addressed fundamental aspects of Vγ2Vδ2 T cells during tuberculosis (TB) and other infections. 3,5-8 Vγ2Vδ2 T cells are the sole γδ T cell subpopulation capable of recognizing phosphoantigens such as microbial (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) and the isoprenoid metabolites isopentenyl pyrophosphate (IPP). 9-11 HMBPP is produced only by the non-mevalonate pathway present in some selected microbes, such as Mycobacterium tuberculosis (Mtb), M bovis BCG and Listeria, whereas IPP can be produced by the mevalonate pathway of cholesterol synthesis in eukaryotic cells. 9,10 Phosphoantigen HMBPP-specific Vγ2Vδ2 T cells, exist only in humans and NHPs. They account for 65%-90% of total peripheral blood γδ T cells in healthy adults, play crucial role in both innate and adaptive immunity, 12-15 and mount major expansion and effector responses during infections with Mtb and other pathogens. 3,5,7,8,16,17 Recent seminal studies in NHP models demonstrate that primary TB infection or phosphoantigen with IL-2 (such as HMBPP + IL-2) administration could specifically induce expansion of Vγ2Vδ2 T cells in vivo; following expansion, they are fast-acting, multi-functional, and protective against infection with high doses of Mtb. 3,5-8 Notably, rapid recall-like expansion of Vγ2Vδ2 T cells correlates with detectable immunity against fatal tuberculosis (TB) after Mtb challenge of bacillus Calmette-Guérin (BCG)-vaccinated macaques. 3 Proof-of-concept (POC) and definitive studies are needed to address the question as to whether human Vγ2Vδ2 T cells play important roles in protective immunity against Mtb and other infections. This question has been long-standing since human γδ T cells were discovered over 30 years ago. This existing gap is largely attributed to the

Bi-specific Antibody Y111, Targeting PD-L1 and CD3 Considerably Enhances the Therapeutic Efficacy of Adoptive Transferred Vγ2Vδ2 T Cells

“…3B). Multifunctional Vγ2Vδ2 T cells have been reported playing central roles in controlling the intracellular bacterial infection and killing transformed tumor cells [1,31]. Indeed, we found the co-stimulation of Y111 and H1975 cells induced larger percentages of effector cells to produce three-and two-cytokines simultaneously (Fig.…”

“…The Vγ2Vδ2 T cells, accounted for about 90% of total γδ T in healthy adults' peripheral blood, appear to be a fast-acting non-conventional T-cell population that contribute to both innate and adaptive immune responses against microbial infections and cancers [1]. Due to their unique biological features, Vγ2Vδ2 T cells have been widely used for adoptive cell immunotherapy in clinical trials to treat a broad range of cancers that display resistance to standard therapies [2].…”

Bispecific Antibody PD-L1 x CD3 Boosts the Anti-Tumor Potency of the Expanded Vγ2Vδ2 T Cells

“…Vg2Vd2 T cells, accounting for about 90% of total gd T cells in the peripheral bloodstreams of healthy adults, appear to be a fast-acting and non-conventional T-cell population that contributes to both innate and adaptive immune responses to microbial infections and cancers (1). Due to their unique biological functions, Vg2Vd2 T cells have been widely used for adoptive cell immunotherapy Abbreviations: ADCC, antibody-dependent cell-mediated cytotoxicity; ATCC, American Type Culture Collection; BsAb, bispecific antibody; CBA, cytometric bead array; CFSE, carboxyfluorescein succinimidyl ester; EGFR, epidermal growth factor receptor; Fab, antigen-binding fragment; ICS, intracellular cytokine staining; IHC, Immunohistochemistry; IFNg, interferon Gamma; NPG, NOD.Cg-Prkdc scid IL2rg tm1Vst /Vst; NSCLC, non-small cell lung cancer; PBMCs, peripheral blood mononuclear cells; PD1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; PI, propidium iodide; TNFa, tumor necrosis factor alpha; SDS-PAGE, sodium dodecyl sulfate-polyacrylamide gel electrophoresis; scFv, single-chain variable fragment.…”

“…Vγ2Vδ2 T cells, accounting for about 90% of total γδ T cells in the peripheral bloodstreams of healthy adults, appear to be a fast-acting and non-conventional T-cell population that contributes to both innate and adaptive immune responses to microbial infections and cancers ( 1 ). Due to their unique biological functions, Vγ2Vδ2 T cells have been widely used for adoptive cell immunotherapy in clinical trials to treat a broad range of cancer patients who have been resistant to the standard therapies ( 2 ).…”

A CD4+CD161+ T-Cell Subset Present in Unexposed Humans, Not Tb Patients, Are Fast Acting Cells That Inhibit the Growth of Intracellular Mycobacteria Involving CD161 Pathway, Perforin, and IFN-γ/Autophagy

“…To date, it remains unknown whether primary CD4+ T-cell population in unexposed humans comprise a fast-acting unconventional T-cell subset that inhibit intracellular Mtb growth or control initial Mtb infection ( 19 , 20 ). It is noteworthy that three major types of unconventional T cells: MAIT, iNKT and γδ T cells share expression of CD161 ( 21 , 22 ).…”