Vaccine-induced antigen-specific regulatory T cells attenuate the antiviral immunity against acute influenza virus infection

Lin, Pin‐Hung; Wong, Weng-In; Wang, Yilan; Hsieh, Meng-Ping; Lu, Chia‐Wen; Liang, Chieh-Yu; Jui, Sung-Hsiang; Wu, Fang–Jing; Chen, Pei‐Jer; Yang, Hung‐Chih

doi:10.1038/s41385-018-0004-9

Cited by 41 publications

(38 citation statements)

References 39 publications

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“…Our study model resembles a preventative vaccination scenario in which an antigen‐specific mTreg pool was established before the host was IAV infected. IAV‐specific mTregs can be induced after vaccination with UV‐inactivated IAV or vaccines containing specific IAV peptides, although such Tregs may dampen the effector T‐cell response a little . It is possible and likely helpful that for future IAV vaccines to incorporate specific strategies to stimulate some IAV‐specific mTregs.…”

Section: Discussionmentioning

confidence: 99%

“…IAV-specific mTregs can be induced after vaccination with UV-inactivated IAV or vaccines containing specific IAV peptides, although such Tregs may dampen the effector T-cell response a little. 38,39 It is possible and likely helpful that for future IAV vaccines to incorporate specific strategies to stimulate some IAV-specific mTregs. It would be more appealing if such vaccine is given via the intranasal route and induces lung-resident mTregs as intranasal administration but not injection of influenza vaccines are more expected to improve the efficacy of influenza vaccines and generating lung-resident memory T cells.…”

Section: Discussionmentioning

confidence: 99%

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Memory regulatory T cells home to the lung and control influenza A virus infection

Zanker

Lock

et al. 2019

Immunol Cell Biol

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Memory regulatory T cells (mTregs) have been demonstrated to persist long‐term in hosts after the resolution of primary influenza A virus (IAV) infection. However, whether such IAV infection‐experienced (IAV‐experienced) mTregs differentiate into a phenotypically and functionally distinct Treg subset and what function they play at the infection site remains poorly defined. In this study, we characterized the phenotype, examined the responsiveness and assessed the suppressive function of IAV‐experienced memory Tregs (mTregs). In comparison with inexperienced naïve Tregs (nTregs), mTregs exhibited elevated expression of CD39, CD69, CD103, cytotoxic T lymphocyte‐associated antigen‐4, leukocyte function‐associated antigen‐1 and programmed cell death‐1 and could be activated in an antigen‐specific manner in vitro and in vivo. When mTregs and nTregs were adoptively cotransferred into recipient mice, mTregs had a competitive advantage in migrating to the IAV‐infected lungs. mTregs were more capable of controlling in vitro proliferation of CD4+ and CD8+ T cells and suppressed CD40 and CD86 upregulation on bone marrow‐derived dendritic cells. Adoptively transferred mTregs, but not adoptively transferred nTregs, significantly attenuated body weight loss, lung pathology and immune cell infiltration into the infected lungs after IAV infection. These results suggest that mTregs generated after IAV infection differentiate into a phenotypically distinct and functionally enhanced Treg subset that can be activated in an antigen‐specific manner to exert immunosuppression. We propose vaccination to induce such mTregs as a potential novel strategy to protect against severe IAV infection.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Memory regulatory T cells home to the lung and control influenza A virus infection

Zanker

Lock

et al. 2019

Immunol Cell Biol

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“…For example, functionally active and virus‐specific FOXP3 + Tregs were induced inhepatitis C virus infection and can provide targeted immune regulation in vivo . It was also reported that the induction of Tregs upon vaccination sometimes attenuates the immunity induced by the vaccine . Interestingly, higher frequency of CD4 + CD25 high Treg cells was detected in some hemophilia patients with FVIII inhibitors, suggesting generation of potential FVIII‐specific Tregs.…”

Section: Discussionmentioning

confidence: 96%

Antigen‐specific in vitro expansion of factor VIII‐specific regulatory T cells induces tolerance in hemophilia A mice

Smith

Lyle

Chen

et al. 2020

Journal of Thrombosis and Haemostasis

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| INTRODUC TI ONHemophilia A (HemA) is a disorder characterized by a deficiency of the blood coagulation factor VIII (FVIII). Patients are treated acutely or prophylactically by protein replacement therapy to restore coagulation function. 1 However, 25% to 30% of patients with severe hemophilia develop alloantibodies to FVIII due to the lack of immune tolerance for the protein. 2 These antibodies are referred to as inhibitors that neutralize the action of FVIII, causing treatment effectiveness to decline with increasing inhibitor titers.Immune tolerance induction (ITI) is currently used to decrease the inhibitory response to FVIII. The variety of ITI dosing schedules Abstract Background: Following protein replacement therapy, one-third of severe hemophilia A patients develop antibodies to factor VIII (FVIII), which also hinders the efficacy of gene therapy. Regulatory T cells (Tregs) have a naturally suppressive function that potentially reduces the immune response to FVIII therapy. Furthermore, antigen-specific Tregs are functionally much more potent than polyclonal cells. Adoptive transfer of antigen-specific Tregs can effectively suppress anti-FVIII antibody responses.Objective: Develop a clinically feasible protocol to enrich and expand Tregs specific to FVIII for suppressing anti-FVIII immune responses.Methods: Regulatory T cells are isolated from FVIII-sensitized mice, sorted on CD25 high markers, and expanded specifically with FVIII, antigen-presenting cells, and interleukin 2 (IL 2). Subsequently, Tregs are further cultured with anti-CD3/anti-CD28 beads, anti-Crry antibodies, and IL 2 to achieve 10-fold to 20-fold expansion. Expanded Tregs are characterized and tested for their suppressive activity in vitro and in vivo. Results:In vitro FVIII-specific suppressive assays indicate that FVIII specifically expanded Tregs are more suppressive than non-specifically expanded and naive Tregs.Adoptive transfer of expanded Tregs into HemA mice showed that FVIII-specifically expanded Tregs are significantly more potent in suppressing anti-FVIII immune responses in FVIII plasmid-treated HemA mice. Moreover, the FVIII-specific immune tolerance is maintained after a secondary challenge with FVIII plasmid. Conclusions:Our results demonstrate that the FVIII-specific sensitization and expansion protocol yields more potent Tregs to suppress anti-FVIII antibody responses and induce long-term tolerance to FVIII, increasing the potential for adoptive Treg cell therapy to modulate anti-FVIII immune responses. K E Y W O R D S Crry, factor VIII, Foxp3, Hemophilia, regulatory T cells | 329 SMITH ET AL. S U PP O RTI N G I N FO R M ATI O N Additional supporting information may be found online in the Supporting Information section. How to cite this article: Smith BM, Lyle MJ, Chen AC, Miao CH. Antigen-specific in vitro expansion of factor VIII-specific regulatory T cells induces tolerance in hemophilia A mice. J Thromb Haemost. 2020;18:328-340. https ://doi.

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“…In the response to the HBV vaccine, a peptide antigen administered intramuscularly, the helper CD4 T-cell function plays a major role [13, 14] and it is well assumed that T-cell exhaustion and senescence related to HIV infection may result in the failure of such response [15]. The involvement of Treg cells in several immunization models is also being studied [16, 17, 18]. The rationale is that Treg cells suppress the proliferation and cytokine secretion of CD4, CD8 T cells and monocytes, dendritic and B cells [19, 20].…”

Section: Discussionmentioning

confidence: 99%

Improved CD4 T-cell profile and inflammatory levels in HIV-infected subjects on maraviroc-containing therapy is associated with better responsiveness to HBV vaccination

Herrero-Fernández

Rosado‐Sánchez

Genebat

et al. 2018

Preprint

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1 on maraviroc-containing therapy is associated with better responsiveness to HBV 2 vaccination. Abstract word count: 250 15 Number of inserts: 5 (3 tables and 2 figures) 16 Number of references: 42 17 ABSTRACT 26Introduction: We previously found that a maraviroc-containing combined 27 antiretroviral therapy (MVC-cART) was associated with a better response to the 28 Hepatitis B Virus (HBV) vaccine in HIV-infected subjects younger than 50 years old. 29 We aimed here to extend our previous analysis including immunological parameters 30 related to inflammation, T-cell and dendritic cell (DC) subsets phenotype and to explore 31 the impact of MVC-cART on these parameters. 32 Methods: We analyzed baseline samples of vaccinated subjects under 50 years old 33 (n=41). We characterized CD4 T-cells according to the distribution of their maturational 34 subsets and the expression of activation, senescence and prone-to-apoptosis markers; we 35 also quantified Treg-cells and main DC subsets. Linear regressions were performed to 36 determine the impact of these variables on the magnitude of vaccine response. Binary 37 logistic regressions were explored to analyze the impact of MVC-cART on 38 immunological parameters. Correlations with the time of MVC exposure were also 39 explored. 40 Results: MVC-cART remained independently associated with HBV-vaccine 41 responsiveness even after adjusting by immunological variables. The 42 %CD4 + CD25 hi FoxP3 + ki67 + and %pDCs were also independently associated. Moreover, 43 HIV-infected subjects on MVC-containing therapy prior to vaccination showed lower 44 inflammatory levels, activated CD4 T-cells and frequency of Treg cells and higher 45 frequency of recent thymic emigrants.46 Conclusion: Treg-cell levels negatively impacted the HBV-vaccine response, whereas 47 higher pDCs levels and a MVC-cART prior to vaccination were associated with better 48 responsiveness. These factors together with the improved phenotypic CD4 T-cell profile 49 and the lower inflammatory levels found in subjects with a MVC-cART prior HBV 50 vaccination could contribute to their enhanced vaccine response. 51 52 Human Inmunodeficiency Virus (HIV)-infected subjects are at high risk for Hepatitis B 53 Virus (HBV) infection and progression of severe, life-threatening hepatic 54 complications, as cirrhosis and hepatocellular carcinoma [1, 2]. To prevent the 55 associated morbimortality, worldwide current guidelines recommend vaccination 56 against HBV in all HIV-infected subjects susceptible to be coinfected by HBV, but the 57 response rates are lower than in HIV non-infected subjects [reviewed in 3]. 58 The best known predictors of vaccine efficacy are undetectable viral load and CD4 T-59 cell counts above 350 cells/mm 3 [3]. Thus, it is well assumed that a successful combined 60 antiretroviral therapy (cART) favors the vaccine response, however, the influence of the 61 type of antiretroviral treatment has been scarcely explored until now. In this line, it was 62 first described that maraviroc (MVC), a CCR5 antagoni...

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Vaccine-induced antigen-specific regulatory T cells attenuate the antiviral immunity against acute influenza virus infection

Cited by 41 publications

References 39 publications

Memory regulatory T cells home to the lung and control influenza A virus infection

Memory regulatory T cells home to the lung and control influenza A virus infection

Antigen‐specific in vitro expansion of factor VIII‐specific regulatory T cells induces tolerance in hemophilia A mice

Improved CD4 T-cell profile and inflammatory levels in HIV-infected subjects on maraviroc-containing therapy is associated with better responsiveness to HBV vaccination

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