Fusion of HCV Nonstructural Antigen to MHC Class II–associated Invariant Chain Enhances T-cell Responses Induced by Vectored Vaccines in Nonhuman Primates

Strategies to enhance the induction of high magnitude T cell responses through vaccination are urgently needed. Major histocompatibility complex (MHC) class II–associated invariant chain (Ii) plays a critical role in antigen presentation, forming MHC class II peptide complexes for the generation of CD4+ T cell responses. Preclinical studies evaluating the fusion of Ii to antigens encoded in vector delivery systems have shown that this strategy may enhance T cell immune responses to the encoded antigen. We now assess this strategy in humans, using chimpanzee adenovirus 3 and modified vaccinia Ankara vectors encoding human Ii fused to the nonstructural (NS) antigens of hepatitis C virus (HCV) in a heterologous prime/boost regimen. Vaccination was well tolerated and enhanced the peak magnitude, breadth, and proliferative capacity of anti-HCV T cell responses compared to non-Ii vaccines in humans. Very high frequencies of HCV-specific T cells were elicited in humans. Polyfunctional HCV-specific CD8+ and CD4+ responses were induced with up to 30% of CD3+CD8+ cells targeting single HCV epitopes; these were mostly effector memory cells with a high proportion expressing T cell activation and cytolytic markers. No volunteers developed anti-Ii T cell or antibody responses. Using a mouse model and in vitro experiments, we show that Ii fused to NS increases HCV immune responses through enhanced ubiquitination and proteasomal degradation. This strategy could be used to develop more potent HCV vaccines that may contribute to the HCV elimination targets and paves the way for developing class II Ii vaccines against cancer and other infections.

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Faculty Opinions recommendation of Peptide-MHC class II dimers as therapeutics to modulate antigen-specific T cell responses in autoimmune diabetes.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1016402.200705 ◽

2003 ◽

Author(s):

Matthias von Herrath

Keyword(s):

T Cell ◽

Mhc Class Ii ◽

Autoimmune Diabetes ◽

T Cell Responses ◽

Class Ii ◽

Cell Responses

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Faculty Opinions recommendation of Cutting edge: Conditional MHC class II expression reveals a limited role for B cell antigen presentation in primary and secondary CD4 T cell responses.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718020496.793480946 ◽

2013 ◽

Author(s):

Tim Manser

Keyword(s):

T Cell ◽

B Cell ◽

Antigen Presentation ◽

Mhc Class Ii ◽

T Cell Responses ◽

Class Ii ◽

Cutting Edge ◽

Cd4 T Cell ◽

Cell Antigen ◽

Cell Responses

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DNA Vaccines Encoding Antigen Targeted to MHC Class II Induce Influenza-Specific CD8+ T Cell Responses, Enabling Faster Resolution of Influenza Disease

Frontiers in Immunology ◽

10.3389/fimmu.2016.00321 ◽

2016 ◽

Vol 7 ◽

Cited By ~ 8

Author(s):

Laura Lambert ◽

Ekaterina Kinnear ◽

Jacqueline U. McDonald ◽

Gunnveig Grodeland ◽

Bjarne Bogen ◽

...

Keyword(s):

T Cell ◽

Mhc Class Ii ◽

Dna Vaccines ◽

T Cell Responses ◽

Cd8 T Cell ◽

Class Ii ◽

Cell Responses

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Mouse Schwann cells activate MHC class I and II restricted T-cell responses, but require external peptide processing for MHC class II presentation

Neurobiology of Disease ◽

10.1016/j.nbd.2009.11.006 ◽

2010 ◽

Vol 37 (2) ◽

pp. 483-490 ◽

Cited By ~ 20

Author(s):

Gerd Meyer zu Hörste ◽

Holger Heidenreich ◽

Anne K. Mausberg ◽

Helmar C. Lehmann ◽

Anneloor L.M.A. ten Asbroek ◽

...

Keyword(s):

T Cell ◽

Schwann Cells ◽

Mhc Class I ◽

Mhc Class Ii ◽

T Cell Responses ◽

Class Ii ◽

Class I ◽

Peptide Processing ◽

Cell Responses

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Induction of EBV–Latent Membrane Protein 1–Specific MHC Class II–Restricted T-Cell Responses against Natural Killer Lymphoma Cells

Cancer Research ◽

10.1158/0008-5472.can-07-3212 ◽

2008 ◽

Vol 68 (3) ◽

pp. 901-908 ◽

Cited By ~ 28

Author(s):

Hiroya Kobayashi ◽

Toshihiro Nagato ◽

Miki Takahara ◽

Keisuke Sato ◽

Shoji Kimura ◽

...

Keyword(s):

T Cell ◽

Membrane Protein ◽

Natural Killer ◽

Mhc Class Ii ◽

T Cell Responses ◽

Class Ii ◽

Latent Membrane Protein ◽

Latent Membrane Protein 1 ◽

Lymphoma Cells ◽

Cell Responses

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Inhibition of T cell response to native low-density lipoprotein reduces atherosclerosis

Journal of Experimental Medicine ◽

10.1084/jem.20092243 ◽

2010 ◽

Vol 207 (5) ◽

pp. 1081-1093 ◽

Cited By ~ 154

Author(s):

Andreas Hermansson ◽

Daniel F.J. Ketelhuth ◽

Daniela Strodthoff ◽

Marion Wurm ◽

Emil M. Hansson ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Mhc Class Ii ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

T Cell Responses ◽

Class Ii ◽

Low Density ◽

Cell Responses ◽

Ldl Particles

Immune responses to oxidized low-density lipoprotein (oxLDL) are proposed to be important in atherosclerosis. To identify the mechanisms of recognition that govern T cell responses to LDL particles, we generated T cell hybridomas from human ApoB100 transgenic (huB100tg) mice that were immunized with human oxLDL. Surprisingly, none of the hybridomas responded to oxidized LDL, only to native LDL and the purified LDL apolipoprotein ApoB100. However, sera from immunized mice contained IgG antibodies to oxLDL, suggesting that T cell responses to native ApoB100 help B cells making antibodies to oxLDL. ApoB100 responding CD4+ T cell hybridomas were MHC class II–restricted and expressed a single T cell receptor (TCR) variable (V) β chain, TRBV31, with different Vα chains. Immunization of huB100tgxLdlr−/− mice with a TRBV31-derived peptide induced anti-TRBV31 antibodies that blocked T cell recognition of ApoB100. This treatment significantly reduced atherosclerosis by 65%, with a concomitant reduction of macrophage infiltration and MHC class II expression in lesions. In conclusion, CD4+ T cells recognize epitopes on native ApoB100 protein, this response is associated with a limited set of clonotypic TCRs, and blocking TCR-dependent antigen recognition by these T cells protects against atherosclerosis.

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