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Cetaceans exhibit remarkable wound healing capabilities. However, the specific immune mechanisms underlying this process, particularly the role of γδ T cells, remains largely unexplored. In ruminants, pigs, and camelids, which are members of the order Cetartiodactyla alongside cetaceans, γδ T cells express a unique receptor called workshop cluster 1 (WC1). Despite cetaceans also belonging to this order, the presence of WC1 in their γδ T cells has not yet been reported. This study aims to investigate the distribution and potential function of γδ T cells in cetacean skin during homeostasis and wound healing. Using immunofluorescence and immunohistochemical staining, we identified γδ TCR + and WC1 + cells in dolphin skin for the first time. These cells are predominantly located in the dermis and blubber, with an increased presence in healing wounds, suggesting their involvement in wound healing rather than pathogen defense. Furthermore, our findings revealed that γδ TCR + cells constitute a small fraction of CD3 + MHCII + cells in dolphin skin, indicating their intricate role in cetacean immunology. Additionally, the appearance of WC1 + cells in cetaceans highlights unique immunological features within Cetartiodactyla. Comparative analysis demonstrates that γδ T cells in dolphins exhibit distinctive morphological and distributional characteristics compared to those in humans, mice, and ruminants, implying species-specific adaptations. These insights contribute to a deeper understanding of cetacean immunology and underscore the potential evolutionary adaptations that support their exceptional wound healing capabilities. Future research on the genomic and functional aspects of γδ T cells in cetaceans is essential to further elucidate their roles in immune response and wound healing., (Copyright © 2025 Elsevier Ltd. All rights reserved.)

γδT cells are unconventional T cells only accounting for 1-5 % of circulating T lymphocytes. Their potent anti-tumor capability has been evidenced by accumulating studies. However, the prognostic value of γδT cells remains not well documented in head and neck squamous cell carcinoma (HNSCC). In this study, we utilized the TCGA HNSCC database to evaluate the infiltration of γδT cells and the association between γδT cells and clinicopathological factors by related gene signature, which were then validated by a total of 100 collected tumor samples from HNSCC patient cohort. Heterogeneity and functional characteristics of distinct infiltrating γδT cell profiles in HNSCC were then investigated based on the scRNA-seq data from the GEO database. We found higher γδT cell gene signature score was significantly associated with longer survival. Cox regression models showed that γδT cell gene signature could serve as an independent prognostic indicator for HNSCC patients. A high level of γδT cell-related gene signature was positively correlated with the infiltration of tumor-infiltrating lymphocytes and immune score. Through scRNA-seq analysis, we identified that γδ + Trm cells and γδ + CTL cells possessed anti-tumor and immunoregulatory properties. Notably, we found a significant association between the presence of these cells and improved survival outcomes. In our cell-cell communication analyses, we identified that γδT cells have the potential to eliminate tumor cells through the secretion of interferon-gamma and granzyme. Collectively, the infiltration of γδT cells may serve as a promising prognostic tool, prompting the consideration of treatment options for patients with HNSCC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Homograft rejection is the main cause of heart transplantation failure. The role of TLR2, a major member of the toll-like receptor (TLR) family, in transplantation rejection is has yet to be elucidated. In this study, we used a mouse model of acute cardiac transplantation rejection to investigate whether the TLR2 signalling pathway can regulate cardiac transplantation rejection by regulating alloreactive IL-17 + γδT (γδT17) cells. We found that the expression of TLR2 on the surface of dendritic cells (DCs) and macrophages increased during acute transplantation rejection. In addition, our investigation revealed that γδT17 cells exert a significant influence on acute cardiac transplantation rejection. TLR2 gene knockout resulted in an increase in alloreactive γδT17 cells in the spleen and heart grafts of recipient mice compared with wild-type recipient mice and an increase in the mRNA expression of IL-17, IL-1β, CCR6, and CCL20 in the heart grafts. In an in vitro experiment, a mixed lymphocyte reaction was conducted to assess the impact of TLR2 deficiency on the generation of γδT17 cells, which further substantiated a significant increase compared to that in wild-type controls. Furthermore, the mixed lymphocyte reaction showed that TLR2 regulated the production of γδT17 cells by regulating the ability of DCs to secrete IL-1β. These results suggest that TLR2 signalling is important for regulating the generation of γδT17 cells after cardiac allograft transplantation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Autoimmune uveitis is a non-infectious, inflammatory intraocular disease that affects the uveal and adjacent tissues. It frequently causes varying degrees of visual loss. Evidence for the strong association between activated γδ T cells and the development of autoimmune uveitis is growing. The innate and adaptive immune response are connected in the early phases by the γδ T cells that contain the γ and δ chains. γδ T cells can identify antigens in a manner that is not constrained by the MHC. When activated by various pathways, γδ T cells can not only secrete pro-inflammatory factors early on (such as IL-17), but they can also promote Th17 cells responses, which ultimately exacerbates autoimmune uveitis. Therefore, we review the mechanisms by which γδ T cells affect autoimmune uveitis in different activation and disease states. Moreover, we also prospect for immunotherapies targeting different γδ T cell-related action pathways, providing a reference for exploring new drug for the treatment of autoimmune uveitis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Vaccination is the most effective medical strategy for disease prevention but there is a need to improve livestock vaccine efficacy. Understanding the structure of the immune system of swine, which are considered a γδ T cell "high" species, and thus, particularly how to engage their γδ T cells for immune responses, may allow for development of vaccine optimization strategies. The propensity of γδ T cells to home to specific tissues, secrete pro-inflammatory and regulatory cytokines, exhibit memory or recall responses and even function as antigen-presenting cells for αβ T cells supports the concept that they have enormous potential for priming by next generation vaccine constructs to contribute to protective immunity. γδ T cells exhibit several innate-like antigen recognition properties including the ability to recognize antigen in the absence of presentation via major histocompatibility complex (MHC) molecules enabling γδ T cells to recognize an array of peptides but also non-peptide antigens in a T cell receptor-dependent manner. γδ T cell subpopulations in ruminants and swine can be distinguished based on differential expression of the hybrid co-receptor and pattern recognition receptors (PRR) known as workshop cluster 1 (WC1). Expression of various PRR and other innate-like immune receptors diversifies the antigen recognition potential of γδ T cells. Finally, γδ T cells in livestock are potent producers of critical master regulator cytokines such as interferon (IFN)-γ and interleukin (IL)-17, whose production orchestrates downstream cytokine and chemokine production by other cells, thereby shaping the immune response as a whole. Our knowledge of the biology, receptor expression and response to infectious diseases by swine γδ T cells is reviewed here., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

γδ T cells are thymus derived heterogeneous and unconventional T- lymphocyte expressing TCR γ (V γ9) and TCRδ (Vδ2) chain and play an important role in connecting innate and adaptive armaments of immune response. These cells can recognize wide ranges of antigens even without involvement of major histocompatibility complex and exert their biological functions by cytotoxicity or activating various types of immune cells. In recent past, γδ T cells have emerged as an important player during protozoa infection and rapidly expand after exposure with them. They have also been widely studied in vaccine induced immune response against many bacterial and protozoan infections with improved clinical outcome. In this review, we will discuss the various roles of γδ T cells in immunity against malaria and leishmaniasis, the two important protozoan diseases causing significant mortality and morbidity throughout the world., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

The major functions of γδ T cells in mammals overlap with those of αβ T cells but differ in that γδ T cells are rapid responders and see different types of antigens. While γδ T cells have been shown to be a major population of circulating lymphocytes in artiodactyl species such as cattle, sheep, and pigs, less is known about these cells in goats, an important agricultural species. We have recently shown that WC1, a γδ T cell-specific family of hybrid pattern recognition receptors/co-receptors, is a multigenic family in goats expanded beyond what occurs in cattle. This study was conducted to address some of the limitations of previous studies in determining the proportions of γδ T cells, WC1 + γδ T cells as well as the WC1.1 + and WC1.2 + subpopulations in blood and to evaluate their responses to various pathogens. Previously, the proportion of caprine γδ T cells was determined using a monoclonal antibody (mAb) 86D that we show here does not react with all γδ T cells thereby underestimating their contribution to the lymphocyte population. Using a mAb reactive with the TCRδ constant region we found the proportion of γδ T cells in blood was not significantly less than that of either CD4 or CD8 T cells and did not decrease with age after 6 months. γδ T cells that expressed WC1 ranged from ~20 to 85% of the total γδ T cells. Less than half of those were classified as WC1.1 + or WC1.2 + by mAb staining thus indicating a third major WC1 + population. We found that naïve γδ T cells proliferated in cultures of PBMC stimulated with antigens of Leptospira or Mycobacterium avium paratuberculosis (MAP) more than they did in control medium cultures or in those stimulated with M. bovis BCG antigens and that the responding γδ T cells included both WC1 + and WC1 - cells. In ex vivo PMA/ionomycin-stimulated cultures of WC1 - γδ T cells but not WC1 + cells produced both IL-17 and IFNγ. In longterm cultures with Leptospira or MAP both WC1 - and WC1 + cells proliferated but only WC1 - γδ T cells produced IL-17. In conclusion, goats have a substantial number of WC1 - and WC1 + γδ T cells in PBMC that do not decrease with animal age after 6 months; both populations respond to bacterial antigens as naïve cells but in these cultures only the WC1 - γδ cells produc IL-17 and IFNγ ., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Restrictions on antimicrobials demand alternative strategies to improve broiler health, such as supplying feed additives which stimulate innate immune cells like natural killer (NK) cells. The main objective of this study was to characterize intestinal NK cells in broiler chickens during embryonic and early life and compare these to NK cells in spleen, blood and bone marrow. Also T-cell subsets were determined. The majority of intestinal NK cells expressed IL-2Rα rather than 20E5 and 5C7, and showed low level of activation. Within intestinal NK cells the activation marker CD107 was mostly expressed on IL-2Rα + cells while in spleen and blood 20E5 + NK cells primarily expressed CD107. High percentages of intestinal CD8αα + , CD8αβ + and from 2 weeks onward also gamma delta T cells were found. Taken together, we observed several intestinal NK subsets in broiler chickens. Differences in NK subsets were mostly observed between organs, rather than differences over time. Targeting these intestinal NK subsets may be a strategy to improve immune-mediated resistance in broiler chickens., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

There is increasing appreciation of the critical pathogenic role of IL-17 in inflammation and autoimmune diseases, which could be produced from both adaptive Th17 cells and innate γδ T cells. Existing evidences suggest that IL-2 is important for in vivo accumulation of IL-17 + γδ T cells, leaving the mechanisms still elusive. Herein, using lupus-prone MRL/lpr mice, we demonstrated that splenic γδ T cells were potent IL-17 producers at the onset of lupus, which could be diminished by in vivo IL-2 neutralization. Additional in vivo results showed that neutralization of IL-2 also significantly deleted the IL-17-producing γδ T cells in ovalbumin (OVA) /CFA-immunized B6 mice. Using splenic γδ T cells from OVA/CFA-immunized B6 mice, we further demonstrated that IL-2 could induce IL-17 production alone or together with IL-1β or IL-23 or anti-TCRγδ. Mechanism studies demonstrated that IL-2 could support the survival of γδ T cells, rather than induce the proliferation. Through specific pharmacologic inhibitor, we demonstrated that IL-2 could maintain that RORγt expression of γδ T cells in a STAT5-dependent manner. Collectively, this study suggested that the interplay between IL and 2 and other pro-inflammatory cytokines could trigger the rapid IL-17 production from innate γδ T cells, thus to orchestrate an inflammatory response before the development of adaptive Th17 cells., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Alopecia areata (AA) is a common alopecia characterized by non-scarring hair loss with the dysregulated immunity. However, the pathogenesis of AA remains to be elucidated. In this study, we identified gene signatures and then analyzed transcription factor-immune regulatory network in AA using integrated bioinformatics methods. Finally, we verified potential target genes in lesions of AA patients using qPCR and immunohistochemistry. Here, 74 differentially expressed genes (DEGs) were identified in AA, which were enriched in immune-related signaling pathway. The immune analysis revealed the infiltration of γδT cells and Macrophages M1 in AA lesion. Next, the expression correlation analysis and ChIP-seq results revealed a transcription factor (EOMEs) regulated network. We found that EOMEs, a T-box transcription factor, may be involved in the immunoregulation in AA via targeting CD8A and BMP2, and it may affect keratinocytes function via regulating GZMK, LYPD6, RNF182, KRTAP5-9 and KRT73 expression. Finally, the mRNA expression of these network genes in AA lesions was confirmed using qPCR. And the increase expression of EOMEs was identified at inflammatory cells at the periphery of hair follicles and partial keratinocytes in AA tissue using immunohistochemistry. In conclusions, our research demonstrated that EOMEs may play a key role in the progression of AA via regulating immune cell infiltration and keratinocytes function, indicating EOMEs as a promising therapeutic target of AA., Competing Interests: Declaration of Competing Interest The authors declared that there is no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Vδ2 T cells represent the major γδ T cell subset in humans and can serve as an important early source of TNF-α and IFN-γ during inflammatory responses. In acute myeloid leukemia (AML) patients receiving allogeneic stem cell transplantation, higher γδ T cell count predicted better prognosis. The impact of PD-1 and TIM-3 expression on the function of Vδ2 T cells is yet unclear. In this study, we showed that the frequencies of PD-1 + TIM-3 - Vδ2 T cells were comparable between healthy controls and AML patients, but the frequencies of PD-1 - TIM-3 + Vδ2 T cells and of PD-1 + TIM-3 + Vδ2 T cells were significantly higher in AML patients than in healthy controls. Both PD-1 and TIM-3 were upregulated upon phosphoantigen + IL-2 activation, but the relative differences in the frequencies of various PD-1 vs. TIM-3 subsets between AML patients and healthy controls remained. Interestingly, among all PD-1 vs. TIM-3 subsets, the PD-1 + TIM-3 - subset presented the highest TNF-α and IFN-γ expression, while the PD-1 + TIM-3 + subset presented the lowest TNF-α and IFN-γ expression. Anti-PD-1 inhibition did not significantly affect the production of TNF-α or IFN-γ, but anti-TIM-3 inhibition and anti-PD-1/TIM-3 dual inhibition significantly elevated the production of TNF-α and IFN-γ. Interestingly, anti-PD-1 blocking antibodies had significantly increased the frequency of TIM-3 + cells in Vδ2 T cells, suggesting a compensatory TIM-3 upregulation. In addition, the levels of PD-L1 and HMGB-1 were significantly higher in AML patients than in healthy subjects. In summary, this study provides knowledge on the cytokine expression patterns by PD-1 and/or TIM-3-expressing Vδ2 T cells in AML patients, and indicates that the upregulation of PD-1 alone is insufficient to indicate functional impairment, and Vδ2 T cells may require anti-TIM-3 inhibition for functional revival., Competing Interests: Declaration of Competing Interest The authors declared that there is no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Psoriasis is an unchecked chronic inflammation characterized by thick, erythematous, and scaly plaques on the skin. The role of innate immune cells in the pathogenesis of psoriasis is well documented. Bruton's tyrosine kinase (BTK) has been reported to execute important signaling functions in innate immune cells such as dendritic cells (DCs) and gamma delta T cells. However, whether inhibition of BTK would lead to modulation of innate immune function in the context of psoriatic inflammation remains largely unexplored. In the present study, we investigated the effect of selective BTK inhibitor, PCI-32765 on inflammatory signaling in CD11c + DCs and gamma delta T cells in imiquimod (IMQ)-induced mouse model of psoriasis-like inflammation. Our results show that IMQ treatment led to induction of p-BTK expression along with concomitant increase in inflammatory cytokines (IL-23, TNF-α) in CD11c + DCs in the skin. Preventive treatment with BTK inhibitor led to significant reversal in IMQ-induced inflammatory changes in CD11c + DCs of skin. Further, there was a significant decrease in dermal IL-17A levels and IL-17A + γδ + T cells after treatment with BTK inhibitor. Furthermore, short treatment of back skin with IMQ led to upregulated expression of p-BTK along with inflammatory cytokines in CD11c + DCs (IL-23, TNF-α) and IL-17A in γδ + T cells which were reversed by BTK inhibitor. Overall, our study proposes that BTK signaling serves a crucial signaling function in innate immune cells in the context of psoriatic inflammation in mice. Therefore, BTK might be a promising therapeutic target to treat psoriatic inflammation., (Copyright © 2020 Elsevier B.V. All rights reserved.)

γδ T cells may be involved in the onset of systemic lupus erythematosus (SLE) though the production of pro-inflammatory cytokines. IL-17 has been shown to play an important role in the pathogenesis of SLE with lupus nephritis (LN). Although some investigations have indicated that γδ T cells are the major producing cells of IL-17 (γδT17 cells), the function of γδT17 cells in SLE with LN has not yet been fully established. In the present study, transcriptome sequencing analysis was performed to identify genes in γδ T cells differentially expressed between SLE patients with LN and healthy subjects. We first showed that IL-17A expression level in SLE patients is higher than in healthy controls, and the most pronounced increase occurred in the SLE patients with LN. The population of γδ T cells was shown to be smaller in SLE patients, but there was no difference between SLE patients and controls with respect to γδT17 cells. Transcriptome sequencing analysis revealed 28 different genes associated with SLE disease among the γδ T cells from SLE patients with LN. In these genes, CaMK4 was further confirmed to be differently expressed in SLE patients. Finally, CaMK4 inhibitor was shown to inhibit the secretion of IL-17A in γδ T cells from SLE with LN. Our results suggest that CaMK4 may participate in the pathogenic mechanism of SLE with LN induced by γδT17 T cells. This constitutes evidence that CaMK4 inhibitors may serve as effective reagents in the treatment of SLE with LN., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Artesunate (ART), a derivative of artemisinin, is a medication to treat malaria. Beyond that, the anti-inflammatory and immunoregulatory activities of ART have been identified in autoimmune diseases. However, whether ART functions in psoriasis-like dermatitis induced by imiquimod (IMQ, a TLR7/8 agonist) is currently unkown. There, we found that the cumulative score, epidermal thickening and expression of Ki-67 of ART-treated BALB/c mice were significantly lower than those in the IMQ psoriatic model group. In addition, ART treatment ameliorated mice from systemic inflammation. Mechanistically, ART reduced γδ T cells in draining lymph nodes, which might be benefit the improvement of dermatitis. These findings suggested that ART could be a promising drug of psoriasis in clinic., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Acute lung injury (ALI) is one of the most serious complications in critically ill patients which often leads to morbidity and mortality. ALI characterized by severe inflammation of lungs occurs due to uncontrolled inflammatory immune response. However, the immunological mechanism(s) are far from being understood. The spleen tyrosine kinase (SYK), a key component of immune receptor signaling, plays a critical role in the modulation of inflammatory signaling in different immune cells. However, its role in ALI remains to be explored. Therefore, in this study, we investigated the effect of R406, a SYK inhibitor in lipopolysaccharide (LPS)-induced ALI mouse model. LPS led to increased SYK expression in neutrophils and gamma delta (γδ) T cells. This was associated with increased neutrophilic airway inflammation, vascular permeability, myeloperoxidase activity in the lung with upregulated expression of NADPH oxidase (NOX2)/MCP-1/TNF-α in neutrophils and IL-17A in γδ T cells/lung. Pulmonary inflammation was associated with higher mortality in mice with ALI. Inhibition of SYK signaling using R406 in the lung led to blockade of neutrophilic airway inflammation, vascular permeability, pro-inflammatory cytokine release and oxidative stress in innate immune cells, i.e. γδ T cells and neutrophils and the lung. R406 administered LPS group had better survival rate than LPS group. This suggests that SYK upregulation in γδ T cells and neutrophils plays an important role in inflammatory process during ALI. In conclusion, R406 exhibited a great potential to block the LPS-induced airway inflammation and mortality which could be developed as a potential future therapy in ALI., (Copyright © 2018 Elsevier B.V. All rights reserved.)

To gain insights into the role of CD3 - /28.4 + intraepithelial lymphocytes-natural killer (CD3 - /28.4 + IEL-NK) cells during infectious bursal disease virus (IBDV) infection, characterisation of the cells was performed following infection with different strains of the virus. In vitro treatment with IL-18 or ionomycin/PMA successfully stimulated and activated the cells via a significant increase in the expression of CD69, B-Lec, CHIR-AB1 and NK-lysin. Similarly, chickens infected with the vaccine strain of IBDV also up-regulated the expression of CD69, B-Lec, CHIR-AB1 and NK-lysin in CD3 - /28.4 + IEL-NK cells up to 3 days post infection (dpi) and down-regulated the expression of the inhibitory receptor B-NK at 3 dpi. On the contrary, infection with the very virulent IBDV (vvIBDV) strain lead to a reduced activation of the cells by down-regulating the expression of the CD69, CHIR-AB1 and NK-lysin especially at 1 dpi. These findings altogether demonstrate the differential activation of CD3 - /28.4 + IEL-NK cells in chicken following infection with the vaccine or very virulent strains of IBDV. The study therefore provides an important clue into the differential pathogenesis of IBDV infection in chicken. Further studies are however required to determine the functional importance of these findings during IBDV vaccination and infection., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Cytokines of the common gamma-chain receptor family, comprising interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15 and IL-21, are vital with respect to organizing and sustaining healthy immune cell functions. Supporting the anti-cancer immune response, these cytokines inspire great interest for their use as vaccine adjuvants and cancer immunotherapies. It is against this background that gamma delta (γδ) T cells, as special-force soldiers and natural contributors of the tumor immunosurveillance, also received a lot of attention the last decade. As γδ T cell-based cancer trials are coming of age, this present review focusses on the effects of the different cytokines of the common gamma-chain receptor family on γδ T cells with respect to boosting γδ T cells as a therapeutic target in cancer immunotherapy. This review also gathers data that IL-15 in particular exhibits key features for augmenting the anti-tumor activity of effector killer γδ T cells whilst overcoming the myriad of immune escape mechanisms used by cancer cells., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

We have shown that the live-attenuated HSV-1 VC2 vaccine strain with mutations in glycoprotein K (gK) and the membrane protein UL20 is unable to establish latency in vaccinated animals and produces a robust immune response capable of completely protecting mice against lethal vaginal HSV-1 or HSV-2 infections. To better understand the immune response generated by vaccination with VC2, we tested its ability to elicit immune responses in rhesus macaques. Vaccinated animals showed no signs of disease and developed increasing HSV-1 and HSV-2 reactive IgG 1 after two booster vaccinations, while IgG subtypes IgG 2 and IgG 3 remained at low to undetectable levels. All vaccinated animals produced high levels of cross protective neutralizing antibodies. Flow cytometry analysis of cells isolated from draining lymph nodes showed that VC2 vaccination stimulated significant increases in plasmablast (CD27 high CD38 high ) and mature memory (CD21 - IgM - ) B cells. T cell analysis on cells isolated from draining lymph node biopsies demonstrated a statistically significant increase in proliferating (Ki67 + ) follicular T helper cells and regulatory CXCR5 + CD8 + cytotoxic T cells. Analysis of plasma isolated two weeks post vaccination showed significant increases in circulating CXCL13 indicating increased germinal center activity. Cells isolated from vaginal biopsy samples collected over the course of the study exhibited vaccination-dependent increases in proliferating (Ki67 + ) CD4 + and CD8 + T cell populations. These results suggest that intramuscular vaccination with the live-attenuated HSV-1 VC2 vaccine strain can stimulate robust IgG 1 antibody responses that persist for >250days post vaccination. In addition, vaccination lead to the maturation of B cells into plasmablast and mature memory B cells, the expansion of follicular T helper cells, and affects in the mucosal immune responses. These data suggest that the HSV VC2 vaccine induces potent immune responses that could help define correlates of protection towards developing an efficacious HSV-1/HSV-2 vaccine in humans., (Copyright © 2016. Published by Elsevier Ltd.)