Cellular and genetic restrictions in the immunoregulatory activity of alpha-fetoprotein. I. Selective inhibition of anti-Ia-associated proliferative reactions.

Alpha-fetoprotein (AFP), a major alpha-globulin component of fetal and newborn sera, has earlier been shown to exert significant immunosuppressive activity in vitro on T-dependent-immune responses. In the present investigation we have examined the effects of AFP on the recognition and proliferation of T lymphocytes responding in mixed leukocyte culture against histocompatibility-associated alloantigens. Fetal-derived AFP could be shown to exert differential effects on both primary and secondary responses ranging from strong inhibition to occasional enhancement, depending on the stimulating antigens. Proliferative responses against major histocompatibility complex (MHC) I region determinants, mediated predominantly by Ly 1 + cells, were markedly suppressed. Suppression was also observed in responses against Mls locus products, an antigenic system whose recognition requires concomitant recognition of I region gene products on the stimulating cells. In contrast, responses against MHC K or D region determinants, mediated predominantly by Ly 2 + cells, were generally unaffected by AFP. Similarly, non-MHC loci alloantigens distinct from Mls locus products also induced T-cell proliferation which was refractive to suppression by AFP. Because neither Ly 1 + nor Ly 2 + cells responding in this latter situation could be inhibited by AFP, we concluded that the mere fact that a T cell expresses a particular Ly phenotype does not predetermine sensitivity to AFP-induced suppression. In any case, AFP exerts a highly selective suppressive activity on I region-associated immune responses. These data may help to resolve the present controversy over the possibility that AFP has an in vivo relevance as an immunosuppressive agent by pointing out the importance of selecting proper genetic situations for study.

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Neutrophil subtypes shape HIV-specific CD8 T-cell responses after vaccinia virus infection

npj Vaccines ◽

10.1038/s41541-021-00314-7 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Mauro Di Pilato ◽

Miguel Palomino-Segura ◽

Ernesto Mejías-Pérez ◽

Carmen E. Gómez ◽

Andrea Rubio-Ponce ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

Vaccinia Virus ◽

Adaptive Immune System ◽

T Cell Responses ◽

Cd8 T Cell ◽

Cell Responses ◽

Adaptive Immune

AbstractNeutrophils are innate immune cells involved in the elimination of pathogens and can also induce adaptive immune responses. Nα and Nβ neutrophils have been described with distinct in vitro capacity to generate antigen-specific CD8 T-cell responses. However, how these cell types exert their role in vivo and how manipulation of Nβ/Nα ratio influences vaccine-mediated immune responses are not known. In this study, we find that these neutrophil subtypes show distinct migratory and motility patterns and different ability to interact with CD8 T cells in the spleen following vaccinia virus (VACV) infection. Moreover, after analysis of adhesion, inflammatory, and migration markers, we observe that Nβ neutrophils overexpress the α4β1 integrin compared to Nα. Finally, by inhibiting α4β1 integrin, we increase the Nβ/Nα ratio and enhance CD8 T-cell responses to HIV VACV-delivered antigens. These findings provide significant advancements in the comprehension of neutrophil-based control of adaptive immune system and their relevance in vaccine design.

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Optimized Adenovirus-Antibody Complexes Stimulate Strong Cellular and Humoral Immune Responses against an Encoded Antigen in Naïve Mice and Those with Preexisting Immunity

Clinical and Vaccine Immunology ◽

10.1128/cvi.05319-11 ◽

2011 ◽

Vol 19 (1) ◽

pp. 84-95 ◽

Cited By ~ 6

Author(s):

Jin Huk Choi ◽

Joe Dekker ◽

Stephen C. Schafer ◽

Jobby John ◽

Craig E. Whitfill ◽

...

Keyword(s):

Immune Response ◽

T Cell ◽

Immune Responses ◽

Neutralizing Antibodies ◽

T Cell Responses ◽

Transduction Efficiency ◽

Virus Antibody ◽

Cell Responses

ABSTRACTThe immune response to recombinant adenoviruses is the most significant impediment to their clinical use for immunization. We test the hypothesis that specific virus-antibody combinations dictate the type of immune response generated against the adenovirus and its transgene cassette under certain physiological conditions while minimizing vector-induced toxicity.In vitroandin vivoassays were used to characterize the transduction efficiency, the T and B cell responses to the encoded transgene, and the toxicity of 1 × 1011adenovirus particles mixed with different concentrations of neutralizing antibodies. Complexes formed at concentrations of 500 to 0.05 times the 50% neutralizing dose (ND50) elicited strong virus- and transgene-specific T cell responses. The 0.05-ND50formulation elicited measurable anti-transgene antibodies that were similar to those of virus alone (P= 0.07). This preparation also elicited very strong transgene-specific memory T cell responses (28.6 ± 5.2% proliferation versus 7.7 ± 1.4% for virus alone). Preexisting immunity significantly reduced all responses elicited by these formulations. Although lower concentrations (0.005 and 0.0005 ND50) of antibody did not improve cellular and humoral responses in naïve animals, they did promote strong cellular (0.005 ND50) and humoral (0.0005 ND50) responses in mice with preexisting immunity. Some virus-antibody complexes may improve the potency of adenovirus-based vaccines in naïve individuals, while others can sway the immune response in those with preexisting immunity. Additional studies with these and other virus-antibody ratios may be useful to predict and model the type of immune responses generated against a transgene in those with different levels of exposure to adenovirus.

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New differentiation pathway for double-negative regulatory T cells that regulates the magnitude of immune responses

Blood ◽

10.1182/blood-2006-10-050625 ◽

2006 ◽

Vol 109 (9) ◽

pp. 4071-4079 ◽

Cited By ~ 64

Author(s):

Dong Zhang ◽

Wei Yang ◽

Nicolas Degauque ◽

Yan Tian ◽

Allison Mikita ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Regulatory T Cells ◽

Cell Surface ◽

Immune Responses ◽

Lymphoid Tissues ◽

Double Negative ◽

Healthy Humans

Abstract Recent studies have demonstrated that in peripheral lymphoid tissues of normal mice and healthy humans, 1% to 5% of αβ T-cell receptor–positive (TCR+) T cells are CD4−CD8− (double-negative [DN]) T cells, capable of down-regulating immune responses. However, the origin and developmental pathway of DN T cells is still not clear. In this study, by monitoring CD4 expression during T-cell proliferation and differentiation, we identified a new differentiation pathway for the conversion of CD4+ T cells to DN regulatory T cells. We showed that the converted DN T cells retained a stable phenotype after restimulation and that furthermore, the disappearance of cell-surface CD4 molecules on converted DN T cells was a result of CD4 gene silencing. The converted DN T cells were resistant to activation-induced cell death (AICD) and expressed a unique set of cell-surface markers and gene profiles. These cells were highly potent in suppressing alloimmune responses both in vitro and in vivo in an antigen-specific manner. Perforin was highly expressed by the converted DN regulatory T cells and played a role in DN T-cell–mediated suppression. Our findings thus identify a new differentiation pathway for DN regulatory T cells and uncover a new intrinsic homeostatic mechanism that regulates the magnitude of immune responses. This pathway provides a novel, cell-based, therapeutic approach for preventing allograft rejection.

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Anti-CD40 Antibody Fused to CD40 Ligand Is a Superagonist Platform for Adjuvant Intrinsic DC-Targeting Vaccines

Frontiers in Immunology ◽

10.3389/fimmu.2021.786144 ◽

2022 ◽

Vol 12 ◽

Author(s):

Valentina Ceglia ◽

Sandra Zurawski ◽

Monica Montes ◽

Mitchell Kroll ◽

Aurélie Bouteau ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

Immune Responses ◽

Class I ◽

Agonist Activity ◽

Cell Immunity ◽

Hiv 1

CD40 is a potent activating receptor expressed on antigen-presenting cells (APCs) of the immune system. CD40 regulates many aspects of B and T cell immunity via interaction with CD40L expressed on activated T cells. Targeting antigens to CD40 via agonistic anti-CD40 antibody fusions promotes both humoral and cellular immunity, but current anti-CD40 antibody-antigen vaccine prototypes require co-adjuvant administration for significant in vivo efficacy. This may be a consequence of dulling of anti-CD40 agonist activity via antigen fusion. We previously demonstrated that direct fusion of CD40L to anti-CD40 antibodies confers superagonist properties. Here we show that anti-CD40-CD40L-antigen fusion constructs retain strong agonist activity, particularly for activation of dendritic cells (DCs). Therefore, we tested anti-CD40-CD40L antibody fused to antigens for eliciting immune responses in vitro and in vivo. In PBMC cultures from HIV-1-infected donors, anti-CD40-CD40L fused to HIV-1 antigens preferentially expanded HIV-1-specific CD8+ T cells versus CD4+ T cells compared to analogous anti-CD40-antigen constructs. In normal donors, anti-CD40-CD40L-mediated delivery of Influenza M1 protein elicited M1-specific T cell expansion at lower doses compared to anti-CD40-mediated delivery. Also, on human myeloid-derived dendritic cells, anti-CD40-CD40L-melanoma gp100 peptide induced more sustained Class I antigen presentation compared to anti-CD40-gp100 peptide. In human CD40 transgenic mice, anti-CD40-CD40L-HIV-1 gp140 administered without adjuvant elicited superior antibody responses compared to anti-CD40-gp140 antigen without fused CD40L. In human CD40 mice, compared to the anti-CD40 vehicle, anti-CD40-CD40L delivery of Eα 52-68 peptide elicited proliferating of TCR I-Eα 52-68 CD4+ T cells producing cytokine IFNγ. Also, compared to controls, only anti-CD40-CD40L-Cyclin D1 vaccination of human CD40 mice reduced implanted EO771.LMB breast tumor cell growth. These data demonstrate that human CD40-CD40L antibody fused to antigens maintains highly agonistic activity and generates immune responses distinct from existing low agonist anti-CD40 targeting formats. These advantages were in vitro skewing responses towards CD8+ T cells, increased efficacy at low doses, and longevity of MHC Class I peptide display; and in mouse models, a more robust humoral response, more activated CD4+ T cells, and control of tumor growth. Thus, the anti-CD40-CD40L format offers an alternate DC-targeting platform with unique properties, including intrinsic adjuvant activity.

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A novel recombinant protein vaccine containing the different E7 proteins of the HPV16, 18, 6, 11 E7 linked to the HIV-1 Tat (47-57) improve cytotoxic immune responses

10.21203/rs.3.rs-195613/v1 ◽

2021 ◽

Author(s):

Tahoora Mousavi ◽

Reza Valadan ◽

Alireza Rafiei ◽

Ali Abbasi ◽

Mohammad Reza Haghshenas

Keyword(s):

T Cell ◽

Immune Responses ◽

Fusion Protein ◽

Protein Vaccine ◽

Term Survival ◽

Ifn Γ ◽

E7 Proteins ◽

Hiv 1

Abstract Objectives Human papillomavirus infection (HPV) is the most common viral infection which is causes of cervical, penal, vulvar, anal and, oropharyngeal cancer. E7 protein of HPV is a suitable target for induction of T cell responses and controlling HPV-related cancer. The aim of the current study was to designed and evaluated a novel fusion protein containing the different E7 proteins of the HPV 16, 18, 6 and 11, linked to the cell-penetrating peptide HIV-1 Tat 49-57, in order to improve cytotoxic immune responses in in-vitro and in-vivo. Results In this study whole sequence of HPV16,18,6,11 E7-Tat (47-57) and HPV16,18,6,11 E7 cloned into the vector and expressed in E.coli (BL21). The purified protein was confirmed by SDS page and western blotting and then injected into the C57BL/6 mice. The efficiency of the fusion protein vaccine was assessed by antibody response assay, cytokine assay (IL-4 and IFN-γ), CD+8 cytotoxicity assay and tumor challenge experiment. Result showed that fusion proteins containing Adjuvant (IFA,CFA) could express higher titer of antibody. Also, we showed that vaccination with E7-Tat and, E7-Tat-ADJ induced high frequencies of E7-specific CD8+ T cells and CD107a expression as well as IFN-γ level and enhanced long-term survival in the therapeutic animal models. Conclusion Our finding suggested that this novel fusion protein vaccine was able to induce therapeutic efficacy and immunogenicity by improving CD8+ T cell in TC-1 tumor bearing mice; so this vaccine may be appreciated for research against HPV and tumor immunotherapies.

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Alterations in the HLA-B*57:01 Immunopeptidome by Flucloxacillin and Immunogenicity of Drug-Haptenated Peptides

Frontiers in Immunology ◽

10.3389/fimmu.2020.629399 ◽

2021 ◽

Vol 11 ◽

Author(s):

Montserrat Puig ◽

Suryatheja Ananthula ◽

Ramesh Venna ◽

Swamy Kumar Polumuri ◽

Elliot Mattson ◽

...

Keyword(s):

T Cell ◽

Bacterial Infections ◽

Cell Function ◽

Human Leukocyte ◽

Drug Induced ◽

Mhc I ◽

Anchor Residue ◽

Drug Molecules

Neoantigen formation due to the interaction of drug molecules with human leukocyte antigen (HLA)-peptide complexes can lead to severe hypersensitivity reactions. Flucloxacillin (FLX), a β-lactam antibiotic for narrow-spectrum gram-positive bacterial infections, has been associated with severe immune-mediated drug-induced liver injury caused by an influx of T-lymphocytes targeting liver cells potentially recognizing drug-haptenated peptides in the context of HLA-B*57:01. To identify immunopeptidome changes that could lead to drug-driven immunogenicity, we used mass spectrometry to characterize the proteome and immunopeptidome of B-lymphoblastoid cells solely expressing HLA-B*57:01 as MHC-I molecules. Selected drug-conjugated peptides identified in these cells were synthesized and tested for their immunogenicity in HLA-B*57:01-transgenic mice. T cell responses were evaluated in vitro by immune assays. The immunopeptidome of FLX-treated cells was more diverse than that of untreated cells, enriched with peptides containing carboxy-terminal tryptophan and FLX-haptenated lysine residues on peptides. Selected FLX-modified peptides with drug on P4 and P6 induced drug-specific CD8+ T cells in vivo. FLX was also found directly linked to the HLA K146 that could interfere with KIR-3DL or peptide interactions. These studies identify a novel effect of antibiotics to alter anchor residue frequencies in HLA-presented peptides which may impact drug-induced inflammation. Covalent FLX-modified lysines on peptides mapped drug-specific immunogenicity primarily at P4 and P6 suggesting these peptide sites as drivers of off-target adverse reactions mediated by FLX. FLX modifications on HLA-B*57:01-exposed lysines may also impact interactions with KIR or TCR and subsequent NK and T cell function.

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Adipose-derived stem cells regulate fibrosis by altering CD4+ T-cell immune responses in fat grafting in a mouse model

10.21203/rs.3.rs-26930/v1 ◽

2020 ◽

Author(s):

Xinyao Chen ◽

Yunzi Chen ◽

Zijue Wang ◽

Ziqing Dong ◽

Yao Yao ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

Fat Grafting ◽

Th2 Cells ◽

Control Group ◽

T Cell Immune Responses ◽

Long Term Retention

Abstract Background Autologous fat grafting is becoming increasingly common worldly. However, the long-term retention of fat grafting is still unpredictable due to the inevitable fibrosis that arises during tissue repair. Fibrosis may be regulated by T-cell immune responses that are influenced by adipose-derived stem cells (ASCs). Accordingly, we hypothesized that overly abundant ASCs might promote fibrosis by promoting T-cell immune responses to adipose tissue. Methods We performed 0.3 ml fat grafts with 104/ml, 106/ml and 108/ml ASCs and control group in C57 BL/6 mice in vivo. We observed retention, fibrosis, T-cell immunity, and macrophage infiltration over 12 weeks. In addition, CD4 + T-helper 1 (Th1) cells and T-helper 2 (Th2) cells were co-cultured with ASCs or ASCs conditioned media (CM) in vitro. We detected the ratio of Th2%/Th1% after 24 and 48 hours. Results In vivo, the retention rate was higher in the 104 group, while even lower in the 108 group with significantly increased inflammation and fibrosis than the control group at week 12. There was no significance between control group and the 106 group. Also, the 108 group increased infiltration of M2 macrophages, CD4 + T-cells and Th2/Th1 ratio. In vitro, the ratio of Th2%/Th1% induced by the ASCs-transwell group was higher than the ASCs-CM group and showed concentration-dependent. Conclusions High concentrations of ASCs in adipose tissue can promote Th1–Th2 shifting, and the excess of Th2 cells might promote the persistence of M2 macrophages and increase the level of fibrosis which lead to a decrease in the long-term retention of fat grafts. In addition, we found that ASCs promoted Th1–Th2 shifting in vitro.

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Augmentation of in vitro humoral immune responses in the mouse by an antibody to IgD.

Journal of Experimental Medicine ◽

10.1084/jem.152.3.493 ◽

1980 ◽

Vol 152 (3) ◽

pp. 493-506 ◽

Cited By ~ 10

Author(s):

F D Finkelham ◽

V L Woods ◽

S B Wilburn ◽

J J Mond ◽

K E Stein ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

Total Serum ◽

Adjuvant Effect ◽

Humoral Immune ◽

Humoral Immune Responses ◽

Almost All ◽

T Cell Help

Heterologous anti-delta-chain antibodies have an adjuvant effect on specific in vivo humoral immune responses to simultaneously, or subsequently, injected antigens in the rat and rhesus monkey. We have used a hybridoma-secreted antibody that binds murine delta-chain of the allotype (4.22aM delta a) to study this phenomenon in the mouse and to investigate the mechanism of this effect. Injection of 4.22aM delta a into BALB/c mice removes almost all surface IgD (sIgD) from splenic B lymphocites. sIgD does not reappear until the serum level of 4.22aM delta a decreased 5-7 d after injection. 4.22aM delta a fails to induce detectable proliferation or to raise total serum Ig levels substantially above control values. However, 4.22aM dalta a injected 24 h before antigen elicits an approximately twofold enhancement of serum IgM and a 3- to 10-fold enhancement of serum IgG anti-trintriphenyl (TNP) antibodies in response to immunization with optimal doses of TNP-Ficoll or TNP-sheep red blood cells (TNP-SRBC). 4.22aM delta a injected 1 wk before or 3 d after TNP-SRBC, however, has no effect on IgG anti-TNP levels. The adjuvant effect of anti-delta-chain antibody was markedly decreased when suboptimal antigen doses were used. Furthermore, even in the case of TNP-Ficoll, a relatively T-independent antigen, the ability of 4.22aM dalta a to enhance the anti-TNP antibody response was T cell dependent. Our data suggest that the binding of anti-delta-chain antibody to cell sIgD may partially activate B lymphocytes and make them more capable of differentiating into antibody-secreting cells when stimulated by antigen-specific T cell help.

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Altered Immune Responses in Interleukin 10 Transgenic Mice

Journal of Experimental Medicine ◽

10.1084/jem.185.12.2101 ◽

1997 ◽

Vol 185 (12) ◽

pp. 2101-2110 ◽

Cited By ~ 196

Author(s):

Amy Hagenbaugh ◽

Sherven Sharma ◽

Steven M. Dubinett ◽

Sherry H.-Y. Wei ◽

Richard Aranda ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Transgenic Mice ◽

Immune Responses ◽

Leishmania Major ◽

Severe Combined Immunodeficiency ◽

Interleukin 10 ◽

Altered Expression

Interleukin (IL)-10 is a pleiotropic cytokine which inhibits a broad array of immune parameters including T helper cell type 1 (Th1) cytokine production, antigen presentation, and antigenspecific T cell proliferation. To understand the consequences of altered expression of IL-10 in immune models of autoimmune disease, the response to infectious agents, and the response to tumors, we developed transgenic mice expressing IL-10 under the control of the IL-2 promoter. Upon in vitro stimulation, spleen cells from unimmunized transgenic mice secrete higher levels of IL-10 and lower amounts of IFN-γ than do controls, although no gross abnormalities were detected in lymphocyte populations or serum Ig levels. Transfer of normally pathogenic CD4+ CD45RBhigh splenic T cells from IL-10 transgenic mice did not cause colitis in recipient severe combined immunodeficiency mice. Furthermore, co-transfer of these transgenic cells with CD4+ CD45RBhigh T cells from control mice prevented disease. Transgenic mice retained their resistance to Leishmania major infection, indicating that their cell-mediated immune responses were not globally suppressed. Lastly, in comparison to controls, IL-10 transgenic mice were unable to limit the growth of immunogenic tumors. Administration of blocking IL-10 mAbs restored in vivo antitumor responses in the transgenic mice. These results demonstrate that a single alteration in the T cell cytokine profile can lead to dramatic changes in immune responses in a manner that is stimulus dependent. These mice will be useful in defining differences in inflammatory conditions and cellular immunity mediated by IL-10.

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