NKp46-expressing human gut-resident intraepithelial Vδ1 T cell subpopulation exhibits high antitumor activity against colorectal cancer

Mikulak, Joanna; Oriolo, Ferdinando; Bruni, Elena; Roberto, Alessandra; Colombo, Federico; Villa, Anna; Bosticardo, Marita; Bortolomai, Ileana; Presti, Elena Lo; Meraviglia, Serena; Dieli, Francesco; Vetrano, Stefania; Danese, Silvio; Bella, Silvia Della; Carvello, Michele; Sacchi, Matteo; Cugini, Giovanni; Colombo, Giovanni; Klinger, Marco; Scocco, Paola; Roncalli, Massimo; Prinz, Immo; Ravens, Sarina; Lorenzo, Biagio Di; Marcenaro, Emanuela; Silva‐Santos, Bruno; Spinelli, Antonino; Mavilio, Domenico

doi:10.1172/jci.insight.125884

Cited by 101 publications

(128 citation statements)

References 61 publications

Supporting

Mentioning

119

Contrasting

Order By: Relevance

“… 12 Recently, NKp46 was shown to be specifically expressed on gut-resident intraepithelial human Vδ1 T cells endowed with potent antitumor activity. 59 Taken together, γδ T cells are uniquely equipped with two independent recognition pathways to sense stressed and transformed cells, i.e., TCRs as well as activating NK receptors. 12 , 16 A schematic overview of the major receptor–ligand interactions involved in the activation of human Vδ2 and non-Vδ2 γδ T cells is shown in Fig.…”

Section: Ligand Recognition By Human γδ T Cellsmentioning

confidence: 99%

Cancer immunotherapy with γδ T cells: many paths ahead of us

et al. 2020

View full text Add to dashboard Cite

γδ T cells play uniquely important roles in stress surveillance and immunity for infections and carcinogenesis. Human γδ T cells recognize and kill transformed cells independently of human leukocyte antigen (HLA) restriction, which is an essential feature of conventional αβ T cells. Vγ9Vδ2 γδ T cells, which prevail in the peripheral blood of healthy adults, are activated by microbial or endogenous tumor-derived pyrophosphates by a mechanism dependent on butyrophilin molecules. γδ T cells expressing other T cell receptor variable genes, notably Vδ1, are more abundant in mucosal tissue. In addition to the T cell receptor, γδ T cells usually express activating natural killer (NK) receptors, such as NKp30, NKp44, or NKG2D which binds to stress-inducible surface molecules that are absent on healthy cells but are frequently expressed on malignant cells. Therefore, γδ T cells are endowed with at least two independent recognition systems to sense tumor cells and to initiate anticancer effector mechanisms, including cytokine production and cytotoxicity. In view of their HLA-independent potent antitumor activity, there has been increasing interest in translating the unique potential of γδ T cells into innovative cellular cancer immunotherapies. Here, we discuss recent developments to enhance the efficacy of γδ T cell-based immunotherapy. This includes strategies for in vivo activation and tumor-targeting of γδ T cells, the optimization of in vitro expansion protocols, and the development of gene-modified γδ T cells. It is equally important to consider potential synergisms with other therapeutic strategies, notably checkpoint inhibitors, chemotherapy, or the (local) activation of innate immunity.

show abstract

Section: Ligand Recognition By Human γδ T Cellsmentioning

confidence: 99%

Cancer immunotherapy with γδ T cells: many paths ahead of us

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Similar innate-like phenotypes can be ascribed to human gut-resident Vγ4 + intestinal epithelial γδ T cells (IELs), that are CD69 + and express the natural cytotoxicity receptors Nkp46 and/or Nkp44 [38,110]. Human Vγ4 + IELs are shaped and selected by the BTNL-like molecules, BTNL3 and BTNL8, that are exclusively expressed in the human gut epithelial [14].…”

Section: Tissue-resident γδ Tcr Repertoiresmentioning

confidence: 91%

“…Notably, an innovative approach of single-cell TCR repertoire analysis of γδ IELs of celiac disease patients noticed a higher TCR repertoire diversity, due to loss of innate-like Vγ4 + IELs, but did not identify public γδ T cell clones that may recognize defined disease-associated ligands [39]. Moreover, in colorectal cancer patients with higher numbers of innate-like cytotoxic Nkp46 + Vγ4Vδ1 + T cells were correlated with a better clinical outcome [110]. Altogether, TCR-seq analysis can be a valuable method to distinguish tissue-resident and circulating γδ T cell clones and characterize adaptive-like versus innate-like expansions of tissue γδ T cells in healthy and diseased individuals.…”

Section: Tissue-resident γδ Tcr Repertoiresmentioning

confidence: 97%

“…Human Vγ4 + IELs are shaped and selected by the BTNL-like molecules, BTNL3 and BTNL8, that are exclusively expressed in the human gut epithelial [14]. TCR repertoire analysis of total or Nkp46 + γδ IELs isolated from healthy tissues gave evidence for a relatively clonal TRG and TRD repertoire, enriched for public Vγ4 + and private Vδ1 + T cell clones [38,39,110]. Importantly, celiac disease leads to a loss of the BTNL-induced Vγ4 + IEL compartment, that cannot be restored after gluten-free diet [38].…”

Section: Tissue-resident γδ Tcr Repertoiresmentioning

confidence: 99%

See 1 more Smart Citation

Human γδ TCR Repertoires in Health and Disease

Fichtner

Ravens

Prinz

2020

Cells

Self Cite

View full text Add to dashboard Cite

The T cell receptor (TCR) repertoires of γδ T cells are very different to those of αβ T cells. While the theoretical TCR repertoire diversity of γδ T cells is estimated to exceed the diversity of αβ T cells by far, γδ T cells are still understood as more invariant T cells that only use a limited set of γδ TCRs. Most of our current knowledge of human γδ T cell receptor diversity builds on specific monoclonal antibodies that discriminate between the two major subsets, namely Vδ2+ and Vδ1+ T cells. Of those two subsets, Vδ2+ T cells seem to better fit into a role of innate T cells with semi-invariant TCR usage, as compared to an adaptive-like biology of some Vδ1+ subsets. Yet, this distinction into innate-like Vδ2+ and adaptive-like Vδ1+ γδ T cells does not quite recapitulate the full diversity of γδ T cell subsets, ligands and interaction modes. Here, we review how the recent introduction of high-throughput TCR repertoire sequencing has boosted our knowledge of γδ T cell repertoire diversity beyond Vδ2+ and Vδ1+ T cells. We discuss the current understanding of clonal composition and the dynamics of human γδ TCR repertoires in health and disease.

show abstract

“…The majority of Vδ1+ cells reside in the gut, liver and other epithelial tissues, and pair with Vγ2, Vγ3, Vγ5, Vγ8, and Vγ9 chains [71,72]. Recent studies have shown that the Vδ1+ that are highly enriched in the gut, preferentially pair with Vγ4, express Nkp46+, have a cytotoxic phenotype and are depleted upon gluten-induced inflammation [73,74]. Vδ1+ cells have been shown to be MHC-independent and involves a highly adaptive yet unconventional form of immunosurveillance.…”

Section: Gamma Delta T Cells Subsetsmentioning

confidence: 99%

The Aging of γδ T Cells

Lau

Fülöp

et al. 2020

Cells

View full text Add to dashboard Cite

In the coming decades, many developed countries in the world are expecting the "greying" of their populations. This phenomenon poses unprecedented challenges to healthcare systems. Aging is one of the most important risk factors for infections and a myriad of diseases such as cancer, cardiovascular and neurodegenerative diseases. A common denominator that is implicated in these diseases is the immune system. The immune system consists of the innate and adaptive arms that complement each other to provide the host with a holistic defense system. While the diverse interactions between multiple arms of the immune system are necessary for its function, this complexity is amplified in the aging immune system as each immune cell type is affected differently-resulting in a conundrum that is especially difficult to target. Furthermore, certain cell types, such as γδ T cells, do not fit categorically into the arms of innate or adaptive immunity. In this review, we will first introduce the human γδ T cell family and its ligands before discussing parallels in mice. By covering the ontogeny and homeostasis of γδ T cells during their lifespan, we will better capture their evolution and responses to age-related stressors. Finally, we will identify knowledge gaps within these topics that can advance our understanding of the relationship between γδ T cells and aging, as well as age-related diseases such as cancer.Their well-characterized roles further imply the physiological importance of age-associated T-cell adaptations, which garners the widespread scientific interest that has contributed to the current depth of T-cell-related investigations [14,15].T cells can essentially be classified into the adaptive arm, although minority subsets exhibit an innate phenotype. Adaptive T cells include those expressing an αβ T cell receptor (TCR) at their surface and "innate-like" T cells are comprised of T cells expressing a γδ TCR, mucosal associated invariant T (MAIT), invariant natural killer T (iNKT) and germline-encoded mycolyl lipid-reactive (GEMT) [16]. This classification is based on their response speed when encountering new antigens and the ability to form memory cells that persist in long-term immunosurveillance. In this review, we will focus on γδ T cells and their contextual importance in cancer immunosurveillance, and on the reactivation of latent infections such as tuberculosis and virus-infected cells, as these topics require consolidation in the literature but are often neglected in the aging context.First, we will describe γδ T cells and their respective ligands in both mice and human. Next, we will analyze γδ T cells from cradle to grave (i.e., development to old age) to understand their aging trajectory during lifespan. Finally, we will suggest future developments that are necessary for our comprehension of how γδ T cells subsets are affected during the aging process. A better understanding of γδ T cell biology should enable scientists to tailor optimized immunotherapy that targets age-associated immune impairments in th...

show abstract

NKp46-expressing human gut-resident intraepithelial Vδ1 T cell subpopulation exhibits high antitumor activity against colorectal cancer

Cited by 101 publications

References 61 publications

Cancer immunotherapy with γδ T cells: many paths ahead of us

Cancer immunotherapy with γδ T cells: many paths ahead of us

Human γδ TCR Repertoires in Health and Disease

The Aging of γδ T Cells

Contact Info

Product

Resources

About