Γδ T-cell Activation Research Articles

Spatial and Single Cell Analyses Reveal Heterogeneity of DNAM-1 Receptor-Ligand Interactions that Instructs Intratumoral γδT-Cell Activity.

The dynamic interplay between tumor cells and γδT cells within the tumor microenvironment (TME) significantly influences disease progression and immunotherapy outcome. Here, we delved into the modulation of γδT-cell activation by tumor cell ligands CD112 and CD155, which interact with the activating receptor DNAM-1 on γδT cells. Spatial and single cell RNA sequencing (scRNA-seq), as well as spatial metabolome analysis, from neuroblastoma (NB) revealed that the expression levels and localization of CD112 and CD155 varied across and within tumors, correlating with differentiation status, metabolic pathways, and ultimately disease prognosis and patient survival. Both in vivo tumor xenograft experiments and in vitro co-culture experiments demonstrated that a high CD112/CD155 expression ratio in tumors enhanced γδT-cell-mediated cytotoxicity, while a low-ratio fostered tumor resistance. Mechanistically, CD112 sustained DNAM-1-mediated γδT-cell activation, whereas CD155 downregulated DNAM-1 expression via TRIM21-mediated ubiquitin proteasomal degradation. By interacting with tumor cells differentially expressing CD112 and CD155, intratumoral γδT cells exhibited varying degrees of activation and DNAM-1 expression, representing three major functional subsets. This study underscores the complexity of tumor-immune crosstalk, offering insights into how tumor heterogeneity shapes the immune landscape.

BTN2A1: A Novel Target to Boost Tumor Killing Capacity of Human γδ T Cells.

γδ T cells have recently raised great interest as effector cells in cancer immunotherapy because of their HLA-independent mode of action and their broad tumor reactivity. To translate the application of γδ T cells into clinically effective immunotherapies, specific tumor targeting and/or boosting of γδ T-cell activation in vivo seem to be a critical step. In this issue, Le Floch and colleagues report a new strategy for enabling γδ T cells to be specifically activated to kill acute lymphoblastic leukemia cells and solid tumor cells using agonistic BTN2A1 antibodies. See related article by Le Floch et al., p. XX .

Identification of a pro-protein synthesis osteosarcoma subtype for predicting prognosis and treatment

Osteosarcoma (OS) is a heterogeneous malignant spindle cell tumor that is aggressive and has a poor prognosis. Although combining surgery and chemotherapy has significantly improved patient outcomes, the prognosis for OS patients with metastatic or recurrent OS has remained unsatisfactory. Therefore, it is imperative to gain a fresh perspective on OS development mechanisms and treatment strategies. After studying single-cell RNA sequencing (scRNA-seq) data in public databases, we identified seven OS subclonal types based on intra-tumor heterogeneity. Subsequently, we constructed a prognostic model based on pro-protein synthesis osteosarcoma (PPS-OS)-associated genes. Correlation analysis showed that the prognostic model performs extremely well in predicting OS patient prognosis. We also demonstrated that the independent risk factors for the prognosis of OS patients were tumor primary site, metastatic status, and risk score. Based on these factors, nomograms were constructed for predicting the 3- and 5-year survival rates. Afterward, the investigation of the tumor immune microenvironment (TIME) revealed the vital roles of γδ T-cell and B-cell activation. Drug sensitivity analysis and immune checkpoint analysis identified drugs that have potential application value in OS. Finally, the jumping translocation breakpoint (JTB) gene was selected for experimental validation. JTB silencing suppressed the proliferation, migration, and invasion of OS cells. Therefore, our research suggests that PPS-OS-related genes facilitate the malignant progression of OS and may be employed as prognostic indicators and therapeutic targets in OS.

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.

Abstract LB347: PLA2G2D/PGD2-PTGDR signaling deficiency restricts the melanoma progression and lung metastasis

Abstract Normal 0 false false false EN-US KO X-NONE/* Style Definitions */table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin-top:0in; mso-para-margin-right:0in; mso-para-margin-bottom:8.0pt; mso-para-margin-left:0in; line-height:107%; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Calibri",sans-serif; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-font-kerning:1.0pt; mso-ligatures:standardcontextual;} Melanoma is a serious form of skin cancer with an approximate incidence more than 160,000 cases and 41,000 melanoma-associated death per annual globally. Malignant Melanoma is more dangerous because of its rapid spread and metastasis if it were not treated at an early stage. The high mortality of malignant melanoma incites an urgent need to refine the current treatments. Phospholipase A2 group IID (PLA2G2D) is an inducible enzyme expressed in myeloid cells, positively associated with immune infiltration through producing anti-inflammatory prostaglandin D2 (PGD2). The aging-related increase of PLA2G2D and PTGDR, a PGD2 receptor, makes them attractive targets for treating aged-related diseases, such as chronic inflammation and cancer diseases. In this study, by using Pla2g2d-/- and Ptgdr-/- mice, we found that PLA2G2D or PTGDR deficiency effectively restricted the in-situ growth and lung metastasis of subcutaneously implanted melanoma B16F10. These benefits are associated with the early enrichment of γδ-T cells in the tumor mass. The activation and accumulation of γδ-T cells can be induced in B16F10-bearing WT mice by the adoptive transfer of Pla2g2d-/- or Ptgdr-/- DCs. Pro-inflammatory characteristics of Pla2g2d-/- or Ptgdr-/- DCs, especially the production of IL-1b, contribute to γδ-T cells recruitment. These tumor-restraining effects were further confirmed in DC-specific PTGDR deficient (zDCcrePtgdrfloxp ) mice. Taken together with the prominent expression of PLA2G2D and PTGDR in human lung cancer tissue, this study demonstrates the potential of PLA2G2D-PGD2/PTGDR signaling-targeted therapy in treating melanoma and lung metastasis. Citation Format: Hima Dhakal, Jian Zheng. PLA2G2D/PGD2-PTGDR signaling deficiency restricts the melanoma progression and lung metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB347.

Abstract SY45-02: Engineering strategies based on receptors derived from gdT cells

Abstract SY45-02: Engineering strategies based on receptors derived from gdT cells

Roles of tumor necrosis factor-like ligand 1A in γδT-cell activation and psoriasis pathogenesis.

Interleukin (IL)-17-producing γδT (γδT17) cells mediate inflammatory responses in barrier tissues. Dysregulated γδT17 cell activation can lead to the overproduction of IL-17 and IL-22 and the development of inflammatory diseases, including psoriasis. IL-23 and IL-1β are known to synergistically activate γδT17 cells, but the regulatory mechanisms of γδT17 cells have not been fully elucidated. This study aimed to reveal the contribution of the inflammatory cytokine tumor necrosis factor-like ligand 1A (TL1A) to γδT17 cell activation and psoriasis development. Anti-TL1A antibody was injected into an imiquimod (IMQ)-induced murine psoriasis model. TL1A receptor expression was analyzed in splenic and dermal γδT cells. γδT cells were tested for cytokine production in vitro and in vivo under stimulation with IL-23, IL-1β, and TL1A. TL1A was applied to a psoriasis model induced by intradermal IL-23 injection. Mice deficient in γδT cells were intradermally injected with IL-23 plus TL1A to verify the contribution of TL1A-dependent γδT-cell activation to psoriasis development. Neutralization of TL1A attenuated γδT17 cell activation in IMQ-treated skin. TL1A induced cytokine production by splenic γδT17 cells in synergy with IL-23. Dermal γδT17 cells constitutively expressed a TL1A receptor at high levels and vigorously produced IL-22 upon intradermal IL-23 and TL1A injection but not IL-23 alone. TL1A exacerbated the dermal symptoms induced by IL-23 injection in wild-type but not in γδT cell-deficient mice. These findings suggest a novel regulatory mechanism of γδT cells through TL1A and its involvement in psoriasis pathogenesis as a possible therapeutic target.

Human chorionic gonadotrophin indirectly activates peripheral γδT cells to produce interleukin-10 during early pregnancy.

The immunomodulatory properties of human chorionic gonadotrophin (hCG) have been identified to be critical for successful pregnancy. However, the effects of hCG on peripheral γδT cells during early pregnancy have not been reported previously. We cocultured the purified γδT cells and peripheral blood mononuclear cells (PBMCs) with early pregnancy-relevant hCG concentrations and investigated the changes in the immune functional characteristics of γδT cells via flow cytometry assays. The ratios of CD69+ and IL-10+ γδT cells were increased in early pregnant women compared to nonpregnant women. γδT cells expressed low levels of the mannose receptor (CD206) instead of the classical hCG/LH receptor for hCG. The direct treatment of purified γδT cells with early pregnancy-relevant hCG concentrations may have no significant effects on their immune functions. Interestingly, when PBMCs were treated with the same broad range of hCG concentrations, the ratios of CD69+ and IL-10+ γδT cells to total γδT cells were significantly increased. Certain early pregnancy-relevant hCG concentrations could enhance the ratios of peripheral CD69+ and IL-10+ γδT cells, contributing to the activation of γδT cells and immunological tolerance during early pregnancy. However, these affects may not be strongly mediated by direct ligand-receptor interactions and they may highly depend on immune microenvironment. Our novel observations propose a perspective into the endocrine-immune dialog that exists between the fetus and maternal immune cells.

Examining the impact of immunosuppressive drugs on antibody-dependent cellular cytotoxicity (ADCC) of human peripheral blood natural killer (NK) cells and gamma delta (γδ) T cells

BackgroundHuman natural killer (NK) cells and gamma delta (γδ) T cells may impact outcomes of solid organ transplantation (SOT) such as lung transplantation (LTx) following the differential engagement of an array of activating and inhibitory receptors. Amongst these, CD16 may be particularly important due to its capacity to bind IgG to trigger antibody-dependent cellular cytotoxicity (ADCC) and the production of proinflammatory cytokines. While the use of immunosuppressive drugs (ISDs) is an integral component of SOT practice, their relative impact on various immune cells, especially γδT cells and CD16-induced functional responses, is still unclear. MethodsThe ADCC responses of peripheral blood NK cells and γδT cells from both healthy blood donors and adult lung transplant recipients (LTRs) were assessed by flow cytometry. Specifically, the degranulation response, as reflected in the expression of CD107a, and the capacity of both NK cells and γδT cells to produce IFN-γ and TNF-α was assessed following rituximab (RTX)-induced activation. Additionally, the effect of cyclosporine A (CsA), tacrolimus (TAC), prednisolone (Prdl) and azathioprine (AZA) at the concentration of 1 ng/ml, 10 ng/ml, 100 ng/ml, and 1000 ng/ml on these responses was also compared in both cell types. ResultsFlow cytometric analyses of CD16 expresion showed that its expression on γδT cells was both at lower levels and more variable than that on peripheral blood NK cells. Nevertheless functional analyses showed that despite these differences, γδT cells like NK cells can be readily activated by engagement with RTX to degranulate and produce cytokines such as IFNg and TNF-a. RTX-induced degranulation by either NK cells or γδT cells from healthy donors was not impacted by co-culture with individual ISDs. However, CsA and TAC but not Prdl and AZA did inhibit the production of IFN-γ and TNF-α by both cell types. Flow cytometric analyses of RTX-induced activation of NK cells and γδT cells from LTRs suggested their capacity to degranulate was not markedly impacted by transplantation with similar levels of cells expressing CD107 pre- and post-LTx. However an impairment in the ability of NK cells to produce cytokines was observed in samples obtained post LTx whereas γδT cell cytokine responses were not significantly impacted. ConclusionsIn conclusion, the findings show that despite differences in the expression levels of CD16, γδT cells like NK cells can be readily activated by engagement with RTX and that in vitro exposure to CsA and TAC (calcineurin inhibitors) had a measurable effect on cytokine production but not degranulation by both NK cells and gdT cells from healthy donors. Finally the observation that in PBMC obtained from LTx recipients, NK cells but not γδT cells exhibited impaired cytokine reponses suggests that transplantation or chronic exposure to ISDs differentially impacts their potential to respond to the introduction of an allograft and/or transplant-associated infections.

Transcriptional analysis of human peripheral blood mononuclear cells stimulated by Mycobacterium tuberculosis antigen.

Mycobacterium tuberculosis antigen (Mtb-Ag) is a polypeptide component with a molecular weight of 10-14 kDa that is obtained from the supernatant of the H37Ra strain after heat treatment. It stimulates the activation and proliferation of γδT cells in the blood to produce an immune response against tuberculosis. Mtb-Ag is therefore crucial for classifying and detecting the central genes and key pathways involved in TB initiation and progression. In this study, we performed high-throughput RNA sequencing of peripheral blood mononuclear cells (PBMC) from Mtb-Ag-stimulated and control samples to identify differentially expressed genes and used them for gene ontology (GO) and a Kyoto Encyclopedia of Genomes (KEGG) enrichment analysis. Meanwhile, we used PPI protein interaction network and Cytoscape analysis to identify key genes and qRT-PCR to verify differential gene expression. Single-gene enrichment analysis (GSEA) was used further to elucidate the potential biological functions of key genes. Analysis of immune cell infiltration and correlation of key genes with immune cells after Mtb-Ag-stimulated using R language. We identified 597 differentially expressed genes in Mtb-Ag stimulated PBMCs. KEGG and GSEA enrichment analyzed the cellular pathways related to immune function, and DEGs were found to be primarily involved in the TNF signaling pathway, the IL-17 signaling pathway, the JAK-STAT signaling pathway, cytokine-cytokine receptor interactions, and the NF-κB signaling pathway. Wayne analysis using GSEA, KEGG, and the protein-protein interaction (PPI) network showed that 34 genes, including PTGS2, IL-1β, IL-6, TNF and IFN-γ etal., were co-expressed in the five pathways and all were up-regulated by Mtb-Ag stimulation. Twenty-four DEGs were identified using qRT-PCR, including fourteen up-regulated genes (SERPINB7, IL20, IFNG, CSF2, PTGS2, TNF-α, IL36G, IL6, IL10, IL1A, CXCL1, CXCL8, IL4, and CXCL3) and ten down-regulated genes (RTN1, CSF1R CD14, C5AR1, CXCL16, PLXNB2, OLIG1, EEPD1, ENG, and CCR1). These findings were consistent with the RNA-Seq results. The transcriptomic features associated with Mtb-Ag provide the scientific basis for exploring the intracellular immune mechanisms against Mtb. However, more studies on these DEGs in pathways associated with Mtb-Ag stimulation are needed to elucidate the underlying pathologic mechanisms of Mtb-Ag during Mtb infection.

MCP-1/CCR2 axis is involved in the regulation of γδT cells in lupus nephritis.

γδT cells are important innate immune cells that are involved in the occurrence and development of autoimmune diseases such as systemic lupus erythematosus (SLE). Lupus nephritis (LN) is a serious complication of SLE, characterized by the accumulation of immune cells (including γδT cells) in the target organs to participate in the disease process. Therefore, clarifying how γδT cells chemotactically migrate to target organs may be a key to developing therapeutic methods against LN. Enzyme-linked immunosorbent assay (ELISA) was used to detect serum levels of chemokines in LN patients and healthy controls. Real-time polymerase chain reaction (RT-PCR) and flow cytometry were used to measure the expression of chemokine receptors on the surface of γδT cells. The chemotactic migration ability of γδT cells was detected by Transwell assay. Signalling pathway activation of γδT cells was detected by Automated Capillary Electrophoresis Immunoassay and flow cytometry. The serum levels of chemokines, including monocyte chemoattractant protein-1 (MCP-1) in LN patients, were significantly increased. CCR2, the receptor of MCP-1, was also highly expressed on the surface of peripheral γδT cells in LN patients. In addition, the exogenous addition of MCP-1 can enhance chemotactic migration of γδT cells in LN patients. MCP-1 could activate STAT3 signalling in LN patients' peripheral γδT cells. γδT cells might participate in the pathogenesis of LN through MCP-1/CCR2 axis. This finding provides new opportunities for developing treatment methods against LN by targeting MCP-1/CCR2 axis.

A diversified role for γδT cells in vector-borne diseases.

Vector-borne diseases have high morbidity and mortality and are major health threats worldwide. γδT cells represent a small but essential subpopulation of T cells. They reside in most human tissues and exert important functions in both natural and adaptive immune responses. Emerging evidence have shown that the activation and expansion of γδT cells invoked by pathogens play a diversified role in the regulation of host-pathogen interactions and disease progression. A better understanding of such a role for γδT cells may contribute significantly to developing novel preventative and therapeutic strategies. Herein, we summarize recent exciting findings in the field, with a focus on the role of γδT cells in the infection of vector-borne pathogens.

Gamma-Delta T-Cell Phenotype and Function in DAA-Treated HIV-HCV Co-Infected and HCV-Mono-Infected Subjects

HIV-HCV co-infected subjects are at risk of liver fibrosis which may be linked to immune imbalances. Direct-acting antivirals (DAAs) represent the mainstay of HCV treatment in co-infected individuals, yet their effects on immune cell populations playing a role in fibrogenesis is unknown. We assessed γδ T-cell phenotype and function, Treg and Th17 frequencies, as well as γ-globulins and B-cell activation in 47 HIV-HCV co-infected and 35 HCV mono-infected individuals prior to and following DAA treatment (SVR12). Γδ T-cell activation decreased in both groups yet persisted at higher levels in the HIV-HCV co-infected subjects. No differences were registered in terms of γδT-cell function. Of note, the Vδ2/Th17 ratio, inversely linked to liver damage, increased significantly in the two groups upon treatment, yet a negative correlation between the Vδ2/Th17 ratio and liver function enzymes was found in the co-infected subjects alone. B-cell activation and γ-globulin levels decreased in both settings, yet B-cell activation remained higher in the HIV-HCV co-infected individuals. In HIV-HCV co-infected and HCV mono-infected participants, the effect of DAA was limited to γδ T- and B-cell activation as well as γ-globulin concentrations and the Vδ2/Th17 ratio, with no changes in γδ T-cell function and Treg frequencies. Importantly, γδ T- and B-cell activation remained at higher levels in the co-infected individuals than in those with HCV mono-infection alone. The persistence of such alterations within these cell subsets may be associated with the risk of hepatic and extrahepatic complications.

Nature products of traditional Chinese medicine provide new ideas in γδT cell for tumor immunotherapy

Abstract Due to the unique features of innate immune cells, the role of γδT cells in tumor immunity has gradually attracted more and more attention. Previous studies have found that γδT cells play a dual role in tumor immunology: tumor-promoting and tumor-controlling. The anti-tumor therapy of γδT cell has made remarkable success in clinical application. Especially in recent years, researchers have provided some novel effective ways such as γδT cell exosomes and adoptive chimeric antigen receptor-γδT cell immunotherapy. However, some problems remain to be solved, such as low expansion rate, poor targeting, and tumor microenvironment limiting the effectiveness of γδT immunotherapy. Traditional Chinese medicine is expected to play a positive role in the body immune-enhancing function, promoting the proliferation and activation of γδT cells, and inducing the differentiation of γδT cells. In this review, we summarize the recent research progress and urgent problems of γδT cell in anti-tumor immunotherapy. Moreover, some new strategies of γδT cell for tumor immunotherapy were proposed.

Reduction effect of oral pravastatin on the acute phase response to intravenous zoledronic acid: protocol for a real-world prospective, placebo-controlled trial

IntroductionZoledronic acid (ZA) has been used as a first-line treatment in patients with osteoporosis (OP) who receive an annual injection of 5 mg. However, side effects of bone pain and...

Reviving human γδT cells from apoptosis induced by IL-12/18 via p-JNK inhibition.

γδT cells recognize and exert cytotoxicity against tumor cells independently of MHC restriction and have antigen presentation and regulatory functions to promote adaptive immune responses. They are considered as potential immune cells for cellular immunotherapy in cancer patients. However, it is challenging to ex vivo expand human γδT cells that have superb effector functions and long-term survival for adoptive cancer therapy. We found that IL-12/18 combination could drastically promote IFN-γ secretion and cytotoxicity in human γδT cells. However, the enhanced activation of human γδT cells is accompanied by increased apoptosis and elevated expressions of co-inhibitory receptors under the stimulation of IL-12/18. We further demonstrated that IL-12/18 induced apoptosis of human γδT cells was in a phosphoantigen or IFN-γ-independent manner. Transcriptomic analysis suggested that IL-12/18-induced apoptosis of human γδT cells was mediated by the activation of JNK pathway. p-JNK inhibitor (SP-600125) treatment effectively revived human γδT cells from the apoptosis induced by IL-12/18 and maintained their enhanced IFN-γ production and cytotoxicity against tumor cells. Our results provide a novel and feasible strategy for ex vivo expansion of cytokine-activated human γδT cells, which could promote the efficacy of γδT cell adoptive immunotherapy in cancer patients.

Zoledronic acid conjugated calcium phosphate nanoparticles for applications in cancer immunotherapy

Zoledronic acid (Zol) is a potent bisphosphonate drug used in cancer immunotherapy due to its ability to activate γδT cells and bring about depletion of tumor-associated macrophages. Zoledronic acid pulsed monocytes are utilized for the activation and proliferation of γδT cells. For adoptive γδT cell transfer, isolated peripheral blood mononuclear cells (PBMC) are treated with Zol under in vitro conditions for γδT cell expansion. Herein, we optimized, zoledronate conjugated calcium phosphate nanoparticles (Zol-nCP) to improve in vitro γδT cell proliferation. PBMC treated with Zol-nCP conjugates resulted in 28.7% enhancement in γδT cell proliferation in comparison to free Zol. In addition, the treatment of RAW 264.7 macrophages with Zol-nCP resulted in 25% enhanced Zol mediated toxicity compared to the bare drug. This enhancement in toxicity to macrophages can be utilized for better depletion of tumor-associated macrophages compared to free Zol. The development of this nanoconjugate may have great potential in enhancing the clinical efficacy of bisphosphonate-mediated cancer immunotherapy.

γδT Cells Are Required for CD8+ T Cell Response to Vaccinia Viral Infection.

Vaccinia virus (VV) is the most studied member of the poxvirus family, is responsible for the successful elimination of smallpox worldwide, and has been developed as a vaccine vehicle for infectious diseases and cancer immunotherapy. We have previously shown that the unique potency of VV in the activation of CD8+ T cell response is dependent on efficient activation of the innate immune system through Toll-like receptor (TLR)-dependent and -independent pathways. However, it remains incompletely defined what regulate CD8+ T cell response to VV infection. In this study, we showed that γδT cells play an important role in promoting CD8+ T cell response to VV infection. We found that γδT cells can directly present viral antigens in the context of MHC-I for CD8+ T cell activation to VV in vivo, and we further demonstrated that cell-intrinsic MyD88 signaling in γδT cells is required for activation of γδT cells and CD8+ T cells. These results illustrate a critical role for γδT cells in the regulation of adaptive T cell response to viral infection and may shed light on the design of more effective vaccine strategies based on manipulation of γδT cells.

Understanding the effects of CMV on γδ T-cell populations in HIV patients starting antiretroviral therapy

Cytomegalovirus (CMV) affects γδ T-cell profiles in healthy individuals and transplant recipients, but the effects of HIV and CMV have not been distinguished in HIV patients. CMV-seropositive Indonesian HIV patients (n = 40) were studied before ART and after six months, alongside healthy controls (n = 20). 50% of patients started ART with detectable CMV DNA. Proportions of Vδ2− γδ T-cells were high in patients and declined on ART, whilst proportions of Vδ2+ γδ T-cells were uniformly low, and correlated inversely with levels of CMV DNA and CMV-reactive antibody. Residual Vδ2+ cells were enriched for markers of terminal differentiation, but this did not associate with CMV metrics. Patients with CMV DNA at baseline showed a direct correlation between CMV reactive-antibody and CD8+ γδ T-cells. Our data are consistent with a role for CMV in the depletion of Vδ2+ γδ T-cells in HIV patients beginning ART, with no consistent evidence of a role for CMV in γδ T-cell activation or differentiation.

Boosting innate and adaptive antitumor immunity via a biocompatible and carrier-free nanovaccine engineered by the bisphosphonates-metal coordination

• First calcium-bisphosphonates coordination nanovaccine that boosts both innate and adaptive antitumor immunity. • The combination of nanovaccine and anti-PD-1 achieved a 50% total disappearance of tumor. • The biocompatible nanocarriers could enlarge the innate immunity of bisphosphonates. A calcium-bisphosphonates coordination nanovaccine system was developed to co-deliver bisphosphonates (BPs), tumor antigens and lipid A. In vitro, BPs, as the main part of the carrier-free nanovaccine, promoted the proliferation of γδT cells and stimulated the secretion of IFN-γ and granzyme B. BPs in nanovaccine were also found to stimulate the proliferation of DCs. In vivo, nanovaccine was injected subcutaneously and accumulated in draining LNs. The nanovaccine enhanced DCs maturation and antigen presenting. Antigen specific cytotoxic T cells were induced, subsequently infiltrated into tumors and triggered tumor cells specific lysis. Besides, the anti-tumor efficacy of the nanovaccine was enhanced after combined with PD-1 antibody. Here, OVA 257–280 was used as a model antigen to evaluate the characteristics, innate and adaptive immune activation effect, in vivo tumor prophylactic and therapeutic efficacy of the nanovaccine. To further investigate the application of CaBPs as a vaccination platform for other antigens, the CaBPs/neoantigens nanovaccine (CaBPs/NAg) which contained a cocktail of tumor associated antigen (Trp2 173–196 ) and neoantigens (M27 and M30) was also tested here. Finally, the PD-1 antibody was applied together with the nanovaccine to further verify the anti-tumor efficacy. Most of tumor vaccines currently focus on inducing adaptive immunity, while the antitumor potential of innate immunity is getting more attentions. In an attempt to recruit both innate and adaptive immunity, bisphosphonates (BPs) as a type of orthopaedics drugs with biosafety was applied in an antitumor vaccine here as an innate immune regulator. BPs and calcium themselves shaped the biodegradable nanocarrier via their coordination (CaBPs), which could load peptide antigens due to its hydrophilicity and be stabilized by surface lipids including a TLR4 agonist (nanovaccine). As results, the incorporation of BPs triggered the proliferation and activation of DCs and innate-like γδT cells, while the nanovaccine enhanced antigen presentation and specific lysis of tumor cells. The combination of nanovaccine and anti-PD-1 achieved a 50% total disappearance of tumor. In a prophylactic study, no any tumor occurred in nanovaccine group during a 110 day study with 3 time tumor challenges. Generally, this study validates the double antitumor immunities and provides a very promising approach for clinic application.