Human Vδ1 Research Articles

Vδ1 T Cells Integrated in Full-Thickness Skin Equivalents: A Model for the Role of Human Skin–Resident γδT Cells

Vδ1 T cells are a subpopulation of γδT cells found in human dermis. In contrast to murine skin-resident γδT cells, much less is known regarding their role and function in skin health and disease. Here we report the successful integration of Vδ1 T cells into long-term fibroblast-derived matrix skin equivalents (SE). We isolated Vδ1 T cells from human blood, where they are rare, and established conditions for the integration and maintenance of the freshly isolated Vδ1 T cells in the SEs. Plated on top of the dermal equivalents (DEs), almost all Vδ1 T cells migrated into the dermal matrix where they exerted their influence on both the DE and the epithelium. Vδ1 T cells contributed to epidermal differentiation as indicated by histology, expression of epidermal differentiation markers and RNAseq expression profile. When complemented with the carcinoma-derived SCC13 cells instead of HaCaT, our data suggest a role for Vδ1 T cells in slowing growth of the tumor cells, as indicated by reduced stratification and changes in gene expression profiles. Together, we demonstrate the successful establishment of human Vδ1 T cell-competent skin and skin carcinoma equivalents (SE, SCE) and provide evidence for molecular and functional consequences of the Vδ1 T cells on their respective environment.

IL-27 maintains cytotoxic Ly6C+ γδ T cells that arise from immature precursors

In mice, γδ-T lymphocytes that express the co-stimulatory molecule, CD27, are committed to the IFNγ-producing lineage during thymic development. In the periphery, these cells play a critical role in host defense and anti-tumor immunity. Unlike αβ-T cells that rely on MHC-presented peptides to drive their terminal differentiation, it is unclear whether MHC-unrestricted γδ-T cells undergo further functional maturation after exiting the thymus. Here, we provide evidence of phenotypic and functional diversity within peripheral IFNγ-producing γδ T cells. We found that CD27+ Ly6C− cells convert into CD27+Ly6C+ cells, and these CD27+Ly6C+ cells control cancer progression in mice, while the CD27+Ly6C− cells cannot. The gene signatures of these two subsets were highly analogous to human immature and mature γδ-T cells, indicative of conservation across species. We show that IL-27 supports the cytotoxic phenotype and function of mouse CD27+Ly6C+ cells and human Vδ2+ cells, while IL-27 is dispensable for mouse CD27+Ly6C− cell and human Vδ1+ cell functions. These data reveal increased complexity within IFNγ-producing γδ-T cells, comprising immature and terminally differentiated subsets, that offer new insights into unconventional T-cell biology.

Ex vivo expansion and activation of Vγ9Vδ2 T cells by CELMoDs in combination with zoledronic acid.

As multiple myeloma (MM) progresses, immune effector cells decrease in number and function and become exhausted. This remains an insurmountable clinical issue that must be addressed by development of novel modalities to revitalize anti-MM immunity. Human Vγ9Vδ2 T (Vδ2+ γδ T) cells serve as the first line of defense against pathogens as well as tumors and can be expanded ex vivo from peripheral blood mononuclear cells (PBMCs) upon treatment with amino-bisphosphonates in combination with IL-2. Here, we demonstrated that next-generation immunomodulators called cereblon E3 ligase modulators (CELMoDs), as well as lenalidomide and pomalidomide, expanded Th1-like Vδ2+ γδ T cells from PBMCs in the presence of zoledronic acid (ZA). However, the expansion of Th1-like Vδ2+ γδ T cells by these immunomodulatory drugs was abolished under IL-2 blockade, although IL-2 production was induced in PBMCs. BTN3A1 triggers phosphoantigen presentation to γδ T-cell receptors and is required for γδ T-cell expansion and activation. ZA but not these immunomodulatory drugs upregulated BTN3A1 in monocytes. These results suggest that immunomodulatory drugs and ZA have cooperative roles in expansion of Th1-like Vδ2+ γδ T cells, and provide the important knowledge for clinical application of human Vδ2+ γδ T cells as effector cells.

Serum vitamin D deficiency is associated with increased risk of γδ T cell exhaustion in HBV-infected patients.

Previous studies have demonstrated that T cell exhaustion is associated with poor clearance of Hepatitis B virus (HBV). However, whether the expression of exhaustion markers on innate-like circulating γδ T cells derived from patients with HBV infection correlates with the serum level of vitamin D is not completely understood. In this study, we found that the frequency of circulating Vδ2+ T cell and serum levels of vitamin 25(OH)D3 were significantly decreased in patients with HBV. And serum 25(OH)D3 levels in HBV-infected patients were negatively correlated with HBV DNA load and PD-1 expression on γδ T cells. Interestingly, 1α,25(OH)2 D3 alleviated the exhaustion phenotype of Vδ2 T cells in HBV-infected patients and promoted IFN-β expression in human cytotoxic Vδ2 T cells in vitro. Collectively, these findings demonstrate that vitamin D plays a pivotal role in reversing γδ T-cell exhaustion and is highly promising target for ameliorating HBV infection.

Deep Characterization of Human γδ T Cell Subsets Defines Lineage-Specific Traits

Abstract Human γδ T cells represent a small fraction of T cells in peripheral blood (1–10%). They constitute a unique subset of T lymphocytes that recognize non-peptide antigens through MHC-independent presentation. Major γδ T cell subsets, Vδ1 and Vδ2 possess distinct tissue localization, antigen recognition, and effector responses. We hypothesized that Vδ1 and Vδ2 T cells possess differences at the gene, phenotypic, and functional level that distinguish them as distinct lineages. Comparisons between each subset have been limited by challenges in isolating sufficient cell numbers for characterization. Through multiparametric flow cytometry we identified phenotypic signatures that defined memory and tissue homing properties specific for each subset. The immune checkpoint marker TIGIT marked a Vδ1 T cell population enriched for higher cytotoxic marker expression. Using a stringent FACS-based isolation method, we compared cytotoxicity and gene expression profiles of highly purified human Vδ1 and Vδ2 cells. Cytotoxicity assays revealed similar killing capacity of Daudi cells possibly through dissimilar mechanisms. Microarray analysis identified shared and subset-specific genetic programs including lower expression of CD3ζ in Vδ1 T cells. Analysis of transcription factors associated with subset-specific gene profiles implicated NFAT in Vδ1 and AhR in Vδ2 T cells as key regulators of ex vivo gene expression. In confirmatory assays, using TCR-dependent and independent stimuli we show higher sensitivity to calcium-mediated NFAT activity in Vδ1 T cells while Vδ2 T cells may require additional activating stimuli. These findings will facilitate further studies into the specific contributions of Vδ1 and Vδ2 T cells to the immune system. NIH NIAID R01 AI125097

Deep characterization of human γδ T cell subsets defines shared and lineage-specific traits.

Under non-pathological conditions, human γδ T cells represent a small fraction of CD3+ T cells in peripheral blood (1-10%). They constitute a unique subset of T lymphocytes that recognize stress ligands or non-peptide antigens through MHC-independent presentation. Major human γδ T cell subsets, Vδ1 and Vδ2, expand in response to microbial infection or malignancy, but possess distinct tissue localization, antigen recognition, and effector responses. We hypothesized that differences at the gene, phenotypic, and functional level would provide evidence that γδ T cell subpopulations belong to distinct lineages. Comparisons between each subset and the identification of the molecular determinants that underpin their differences has been hampered by experimental challenges in obtaining sufficient numbers of purified cells. By utilizing a stringent FACS-based isolation method, we compared highly purified human Vδ1 and Vδ2 cells in terms of phenotype, gene expression profile, and functional responses. We found distinct genetic and phenotypic signatures that define functional differences in γδ T cell populations. Differences in TCR components, repertoire, and responses to calcium-dependent pathways suggest that Vδ1 and Vδ2 T cells are different lineages. These findings will facilitate further investigation into the ligand specificity and unique role of Vδ1 and Vδ2 cells in early immune responses.

Exhausted intratumoral Vδ2− γδ T cells in human kidney cancer retain effector function

Gamma delta (γδ) T cells reside within human tissues including tumors, but their function in mediating antitumor responses to immune checkpoint inhibition is unknown. Here we show that kidney cancers are infiltrated by Vδ2− γδ T cells, with equivalent representation of Vδ1+ and Vδ1− cells, that are distinct from γδ T cells found in normal human tissues. These tumor-resident Vδ2− T cells can express the transcriptional program of exhausted αβ CD8+ T cells as well as canonical markers of terminal T-cell exhaustion including PD-1, TIGIT and TIM-3. Although Vδ2− γδ T cells have reduced IL-2 production, they retain expression of cytolytic effector molecules and co-stimulatory receptors such as 4-1BB. Exhausted Vδ2− γδ T cells are composed of three distinct populations that lack TCF7, are clonally expanded and express cytotoxic molecules and multiple Vδ2− T-cell receptors. Human tumor-derived Vδ2− γδ T cells maintain cytotoxic function and pro-inflammatory cytokine secretion in vitro. The transcriptional program of Vδ2− T cells in pretreatment tumor biopsies was used to predict subsequent clinical responses to PD-1 blockade in patients with cancer. Thus, Vδ2− γδ T cells within the tumor microenvironment can contribute to antitumor efficacy.

Anti-PD1 does not improve pyroptosis induced by γδ T cells but promotes tumor regression in a pleural mesothelioma mouse model.

Mesothelioma is an aggressive tumor in the pleural cavity that is difficult to treat. Diagnosis is usually late with minimal treatment options available for the patients and with unfavorable outcomes. However, recent advances in immunotherapy using γδ T cells may have potential against mesothelioma, given its ample tumoricidal and tumor-migratory properties could allow its infiltration to the widespread tumor mass. Thus, we hypothesize that Vδ2 T cells can perform cytotoxic activities against mesothelioma especially when combined with immune checkpoint blocker against PD-1. Human Vδ2 T cells were expanded from peripheral blood mononuclear cells using Tetrakis-pivaloyloxymethyl 2-(thiazole-2-ylamino) ethylidene-1,1-bisphosphonate (PTA) plus IL-2 for 13 days, before used to test for cytotoxicity against mesothelioma cell lines. Mesothelioma-bearing mice was established by Intrapleural administration of mesothelioma cell lines to test for the efficacy of Vδ2 T cells plus anti-PD-1 antibody combination treatment. Pyroptosis was evaluated by cell morphology, western blot analysis, and ELISA experiments. Flow cytometry was used to examine expression of BTN2A1, BTN3A1, PD-L1, PD-L2 on mesothelioma cell lines. Immunofluorescence staining was performed to detect Vδ2 T cells post adoptive transfer and characteristics of pyroptosis in ex vivo mesothelioma tissue sections. Indeed, our data demonstrated that Vδ2 T cells killing mesothelioma can be enhanced by anti-PD-1 antibody in vitro, especially for high PD-1 expressing cells, and in vivo in the intrapleural mesothelioma mice model established by us. Adoptive transfer of Vδ2 T cells into these mice leads to tumor regression by 30-40% compared to control. Immunofluorescence of the tumor section confirmed infiltration of Vδ2 T cells into the tumor, especially to cells with BTN2A1 expression (a Vδ2 T cell activating molecule) despite PD-L1 co-localization. Interestingly, these cells co-expressed cleaved gasdermin D, suggesting that pyroptosis was induced by Vδ2 T cells. This was verified by Vδ2 T/mesothelioma co-culture experiments demonstrating membrane ballooning morphology, increased cleaved caspase-3 and gasdermin E, and upregulated IL-1β and IL-18. Vδ2 T cells plus anti-PD1 exhibited cytotoxicity against mesothelioma in vivo. However, we found no advantage for anti-PD-1 against PD-1 high expressing Vδ2 T cells in promoting pyroptosis. Taken together, our work demonstrated that Vδ2 T cells combined with anti-PD-1 antibody can be developed as a potential combination immunotherapy for mesothelioma.

Human Vδ2 T Cells and Their Versatility for Immunotherapeutic Approaches.

Gamma/delta (γδ) T cells are innate-like immune effectors that are a critical component linking innate and adaptive immune responses. They are recognized for their contribution to tumor surveillance and fight against infectious diseases. γδ T cells are excellent candidates for cellular immunotherapy due to their unique properties to recognize and destroy tumors or infected cells. They do not depend on the recognition of a single antigen but rather a broad-spectrum of diverse ligands through expression of various cytotoxic receptors. In this manuscript, we review major characteristics of the most abundant circulating γδ subpopulation, Vδ2 T cells, their immunotherapeutic potential, recent advances in expansion protocols, their preclinical and clinical applications for several infectious diseases and malignancies, and how additional modulation could enhance their therapeutic potential.

A CMV-induced adaptive human Vδ1+ γδ T cell clone recognizes HLA-DR.

The innate and adaptive roles of γδ T cells and their clonal γδ T cell receptors (TCRs) in immune responses are still unclear. Recent studies of γδ TCR repertoire dynamics showed massive expansion of individual Vδ1+ γδ T cell clones during viral infection. To judge whether such expansion is random or actually represents TCR-dependent adaptive immune responses, information about their cognate TCR ligands is required. Here, we used CRISPR/Cas9-mediated screening to identify HLA-DRA, RFXAP, RFX5, and CIITA as required for target cell recognition of a CMV-induced Vγ3Vδ1+ TCR, and further characterization revealed a direct interaction of this Vδ1+ TCR with the MHC II complex HLA-DR. Since MHC II is strongly upregulated by interferon-γ, these results suggest an inflammation-induced MHC-dependent immune response of γδ T cells.

Abstract CT525: GDX012U-001 A phase 1, open-label, dose escalation, and dose expansion study to assess the safety, tolerability, and preliminary antileukemic activity of GDX012 in patients with MRD positive AML

Abstract Background: The presence of minimal residual disease (MRD) in patients that are in complete remission (CR) is associated with an increased risk of relapse and shorter survival in acute myeloid leukemia (AML). Eradication of MRD may improve outcomes for patients with AML; however, to date, therapeutic strategies that target MRD in AML are limited. Vδ1+ γδ T cells are a subset of γδ T cells, that recognize malignant cells through expression of a diverse repertoire of natural cytotoxicity receptors (NCRs) that interact with cognate stress ligands specifically upregulated on diseased cells. Upon target cell recognition, Vδ1+ γδ T cells mediate anti-tumor activity through the direct lysis of transformed cells. The therapeutic potential of human Vδ1+ γδ T cells for the treatment of AML is supported by published preclinical data that show strong and broad antileukemic activity of Vδ1+ γδ T cells in vitro and in vivo (Almeida et al 2016; Di Lorenzo et al 2019). GammaDelta Therapeutics has developed GDX012, a novel allogeneic cell therapy that is enriched for Vδ1+ γδ T cells for the treatment of AML. The cryopreserved drug product is manufactured from a healthy donor leukapheresis that has undergone αβ T cell depletion prior to expansion. GDX012 is a viable (>70% live), pure (CD45 >90%) suspension for IV infusion consisting mainly of Vδ1+ γδ T cells (>60%) expressing a variety of cellular markers that contribute to their function, recognition and targeting of malignant cells. Analysis of the biodistribution of GDX012 in therapeutic murine xenograft models further supports the clinical application of GDX012. When administered systemically, GDX012 shows homing to the bone marrow and is detected for at least 28 days. This suggests that, in addition to high cytotoxic activity against AML blasts, GDX012 also has the capacity to home to and persist in the specific niche where MRD is detected. Study design: This phase 1, open-label, first-in-human study is comprised of two parts 1) Dose Escalation using 3 + 3 design to sequentially evaluate 4 doses of GDX012; 2) Dose Expansion including at least 10 additional patients at the MTD. The primary objective is to determine safety, tolerability, and the MTD of GDX012. The secondary objective is to evaluate the preliminary antileukemic activity of GDX012 based on detection of MRD in bone marrow. Exploratory objectives will evaluate the kinetics of GDX012 and infiltration in bone marrow and assessment of cytokines in blood and bone marrow. Key eligibility criteria include patients aged ≥18 years of age with histologically confirmed AML who are MRD positive by flow cytometry. Patients must be in first or subsequent CR or CR with incomplete hematological recovery. Eligible patients will undergo lymphodepletion with fludarabine for 4 days and cyclophosphamide for 3 days followed by infusion of GDX012. Patients will be followed for safety for at least 100 days post GDX012 infusion. Antileukemic activity will be evaluated from the bone marrow biopsy at Day 30. Up to 34 patients will be enrolled across 6 US sites. Recruitment to Cohort 1 is ongoing. Clinical trial registry number: NCT05001451 Citation Format: Lisa J. Knowles, Mohsan Malik, Oliver Nussebaumer, Alice Brown, Sandra van Wetering, Michael Koslowski. GDX012U-001 A phase 1, open-label, dose escalation, and dose expansion study to assess the safety, tolerability, and preliminary antileukemic activity of GDX012 in patients with MRD positive AML [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT525.

A local human Vδ1 T cell population is associated with survival in nonsmall-cell lung cancer

Murine tissues harbor signature γδ T cell compartments with profound yet differential impacts on carcinogenesis. Conversely, human tissue-resident γδ cells are less well defined. In the present study, we show that human lung tissues harbor a resident Vδ1 γδ T cell population. Moreover, we demonstrate that Vδ1 T cells with resident memory and effector memory phenotypes were enriched in lung tumors compared with nontumor lung tissues. Intratumoral Vδ1 T cells possessed stem-like features and were skewed toward cytolysis and helper T cell type 1 function, akin to intratumoral natural killer and CD8+ T cells considered beneficial to the patient. Indeed, ongoing remission post-surgery was significantly associated with the numbers of CD45RA−CD27− effector memory Vδ1 T cells in tumors and, most strikingly, with the numbers of CD103+ tissue-resident Vδ1 T cells in nonmalignant lung tissues. Our findings offer basic insights into human body surface immunology that collectively support integrating Vδ1 T cell biology into immunotherapeutic strategies for nonsmall cell lung cancer.

Transcriptional profiling of human Vδ1 Tcells reveals a pathogen-driven adaptive differentiation program.

SUMMARYγδ T cells are generally considered innate-like lymphocytes, however, an ‘‘adaptive-like’’ γδ compartment has now emerged. To understand transcriptional regulation of adaptive γδ T cell immunobiology, we combined single-cell transcriptomics, T cell receptor (TCR)-clonotype assignment, ATAC-seq, and immunophenotyping. We show that adult Vδ1+ T cells segregate into TCF7+LEF1+Granzyme Bneg (Tnaive) or T-bet+Eomes+ BLIMP-1+Granzyme B+ (Teffector) transcriptional subtypes, with clonotypically expanded TCRs detected exclusively in Teffector cells. Transcriptional reprogramming mirrors changes within CD8+ αβ T cells following antigen-specific maturation and involves chromatin remodeling, enhancing cytokine production and cytotoxicity. Consistent with this, in vitro TCR engagement induces comparable BLIMP-1, Eomes, and T-bet expression in naive Vδ1+ and CD8+ T cells. Finally, both human cytomegalovirus and Plasmodium falciparum infection in vivo drive adaptive Vδ1 T cell differentiation from Tnaive to Teffector transcriptional status, alongside clonotypic expansion. Contrastingly, semi-invariant Vγ9+Vδ2+ T cells exhibit a distinct ‘‘innate-effector’’ transcriptional program established by early childhood. In summary, adaptive-like γδ subsets undergo a pathogen-driven differentiation process analogous to conventional CD8+ T cells.

γδ T cell IFNγ production is directly subverted by Yersinia pseudotuberculosis outer protein YopJ in mice and humans.

Yersinia pseudotuberculosis is a foodborne pathogen that subverts immune function by translocation of Yersinia outer protein (Yop) effectors into host cells. As adaptive γδ T cells protect the intestinal mucosa from pathogen invasion, we assessed whether Y. pseudotuberculosis subverts these cells in mice and humans. Tracking Yop translocation revealed that the preferential delivery of Yop effectors directly into murine Vγ4 and human Vδ2+ T cells inhibited anti-microbial IFNγ production. Subversion was mediated by the adhesin YadA, injectisome component YopB, and translocated YopJ effector. A broad anti-pathogen gene signature and STAT4 phosphorylation levels were inhibited by translocated YopJ. Thus, Y. pseudotuberculosis attachment and translocation of YopJ directly into adaptive γδ T cells is a major mechanism of immune subversion in mice and humans. This study uncovered a conserved Y. pseudotuberculosis pathway that subverts adaptive γδ T cell function to promote pathogenicity.

Costimulation of γδTCR and TLR7/8 promotes Vδ2 T-cell antitumor activity by modulating mTOR pathway and APC function

BackgroundGamma delta (γδ) T cells are attractive effector cells for cancer immunotherapy. Vδ2 T cells expanded by zoledronic acid (ZOL) are the most commonly used γδ T cells for adoptive...

NKG2A expression identifies a subset of human Vδ2 Tcells exerting the highest antitumor effector functions.

Human Vδ2 cells are innate-like γδ T effectors performing potent immune surveillance against tumors. The constitutive expression of NKG2A identifies a subset of Vδ2 Tcells licensed with an intrinsic hyper-responsiveness against cancer. Indeed, the transcriptomic profiles of NKG2A+ and NKG2A- cells characterize two distinct "intralineages" of Vδ2T lymphocytes that appear early during development, keep their phenotypes, and show self-renewal capabilities in adult life. The hyper-responsiveness of NKG2A+ Vδ2 Tcells is counterbalanced by the inhibitory signaling delivered by human leukocyte antigen E (HLA-E) expressed on malignant cells as a tumor-escape mechanism. However, either masking or knocking out NKG2A restores the capacity of Vδ2 Tcells to exert the highest effector functions even against HLA-E+ tumors. This is highly relevant in the clinic, as the different degrees of engagement of the NKG2A-HLA-E checkpoint in hepatocellular carcinoma, glioblastoma, and non-small cell lung cancer directly impact patients' overall survival. These findings open avenues for developing combined cellular and immunologic anticancer therapies.

Adaptive γδ T cell function is directly subverted by the Yersinia pseudotuberculosis outer protein YopJ

Abstract Vγ4 T cells are an unconventional subset of T cells that protect the intestinal mucosa from pathogen invasion and capable of anamnestic responses. Yersinia pseudotuberculosis (Yptb) is a foodborne pathogen that invades through the intestinal mucosa and subverts immune function by translocation of Yersiniaouter protein (Yop) effectors into target cells. In this study, we evaluated the response of adaptive Vγ4 T cells to Yptb to determine if adaptive γδ T cells are a target of immune subversion. Tracking Yptb translocation of Yop effectors through a FRET-based reporter assay revealed targeted and preferential delivery of Yop effectors directly into adaptive γδ T cells inhibited anti-microbial IFNγ production. Using a series of recombinant Yptb deficient or defective in numerous pathogenicity genes revealed that direct subversion of the adaptive γδ T cell IFNγ response was mediated by the adhesion molecule YadA, the injectosome component YopB, and the YopJ effector. Thus, Yptb attachment and translocation of YopJ directly into adaptive γδ T cells is a major mechanism of γδ T cell subversion. RNA-Seq of adaptive γδ T cells revealed that a broad anti-pathogen gene signature was inhibited by translocation of YopJ and suggested a role of the STAT4 pathway in this process. Indeed, IL-12p40 promoted the adaptive γδ T cell IFNγ response and YopJ limited STAT4 phosphorylation levels. Importantly, circulating human Vδ2+T cells were similarly targeted and inhibited by the YopJ effector, highlighting a novel and conserved Yptb pathway that subverts adaptive γδ T cell function.

Diversity in recognition and function of human γδ T cells.

As interest increases in harnessing the potential power of tissue-resident cells for human health and disease, γδ T cells have been thrust into the limelight due to their prevalence in peripheral tissues, their sentinel-like phenotypes, and their unique antigen recognition capabilities. This review focuses primarily on human γδ T cells, highlighting their distinctive characteristics including antigen recognition, function, and development, with an emphasis on where they differ from their αβ T cell comparators, as well as from γδ T cell populations in the mouse. We review the antigens that have been identified thus far to regulate members of the human Vδ1 population and discuss what players are involved in transducing phosphoantigen-mediated signals to human Vγ9Vδ2 T cells. We also briefly review distinguishing features of these cells in terms of TCR signaling, use of coreceptor and costimulatory molecules and their development. These cells have great potential to be harnessed in a clinical setting, but caution must be taken to understand their unique capabilities and how they differ from the populations to which they are commonly compared.

Imperfect storm: is interleukin-33 the Achilles heel of COVID-19?

The unique cytokine signature of COVID-19 might provide clues to disease mechanisms and possible future therapies. Here, we propose a pathogenic model in which the alarmin cytokine, interleukin (IL)-33, is a key player in driving all stages of COVID-19 disease (ie, asymptomatic, mild–moderate, severe–critical, and chronic–fibrotic). In susceptible individuals, IL-33 release by damaged lower respiratory cells might induce dysregulated GATA-binding factor 3-expressing regulatory T cells, thereby breaking immune tolerance and eliciting severe acute respiratory syndrome coronavirus 2-induced autoinflammatory lung disease. Such disease might be initially sustained by IL-33-differentiated type-2 innate lymphoid cells and locally expanded γδ T cells. In severe COVID-19 cases, the IL-33–ST2 axis might act to expand the number of pathogenic granulocyte–macrophage colony-stimulating factor-expressing T cells, dampen antiviral interferon responses, elicit hyperinflammation, and favour thromboses. In patients who survive severe COVID-19, IL-33 might drive pulmonary fibrosis by inducing myofibroblasts and epithelial–mesenchymal transition. We discuss the therapeutic implications of these hypothetical pathways, including use of therapies that target IL-33 (eg, anti-ST2), T helper 17-like γδ T cells, immune cell homing, and cytokine balance.

Activation of Human Vδ2+ γδ T Cells by Staphylococcus aureus Promotes Enhanced Anti-Staphylococcal Adaptive Immunity.

Murine studies have shown the potential for γδ T cells to mediate immunity to Staphylococcus aureus in multiple tissue settings by the secretion of diverse cytokines. However, the role played by γδ T cells in human immune responses to S. aureus is almost entirely unknown. In this study, we establish the capacity of human Vδ2+ γδ T cells for rapid activation in response to S. aureus In coculture with S. aureus-infected monocyte-derived dendritic cells (DCs), Vδ2+ cells derived from peripheral blood rapidly upregulate CD69 and secrete high levels of IFN-γ. DCs mediate this response through direct contact and IL-12 secretion. In turn, IFN-γ released by Vδ2+ cells upregulates IL-12 secretion by DCs in a positive feedback loop. Furthermore, coculture with γδ T cells results in heightened expression of the costimulatory molecule CD86 and the lymph node homing molecule CCR7 on S. aureus-infected DCs. In cocultures of CD4+ T cells with S. aureus-infected DCs, the addition of γδ T cells results in heightened CD4+ T cell activation. Our findings identify γδ T cells as potential key players in the early host response to S. aureus during bloodstream infection, promoting enhanced responses by both innate and adaptive immune cell populations, and support their consideration in the development of host-directed anti-S. aureus treatments.