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C3d adjuvant effects are mediated through the activation of C3d-specific autoreactive T cells
Complement fragment C3d covalently attached to antigens enhances immune responses, particularly for antigens lacking T cell epitopes. Enhancement has been attributed to receptor cross-linking between complement receptor CR2 (CD21) and polysaccharide antigen to surface IgM on naïve B cells. Paradoxic...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4323994/ https://www.ncbi.nlm.nih.gov/pubmed/25385064 http://dx.doi.org/10.1038/icb.2014.89 |
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author | De Groot, Anne S. Ross, Ted M. Levitz, Lauren Messitt, Timothy J. Tassone, Ryan Boyle, Christine M. Vincelli, Amber J. Moise, Leonard Martin, William Knopf, Paul M. |
author_facet | De Groot, Anne S. Ross, Ted M. Levitz, Lauren Messitt, Timothy J. Tassone, Ryan Boyle, Christine M. Vincelli, Amber J. Moise, Leonard Martin, William Knopf, Paul M. |
author_sort | De Groot, Anne S. |
collection | PubMed |
description | Complement fragment C3d covalently attached to antigens enhances immune responses, particularly for antigens lacking T cell epitopes. Enhancement has been attributed to receptor cross-linking between complement receptor CR2 (CD21) and polysaccharide antigen to surface IgM on naïve B cells. Paradoxically, C3d has still been shown to increase immune responses in CD21 KO mice, suggesting that an auxiliary activation pathway exists. In prior studies, we demonstrated the CD21-independent C3d adjuvant effect might be due to T cell recognition of C3d T helper epitopes processed and presented by MHC class II on the B cell surface. C3d peptide sequences containing concentrated clusters of putative human C3 T cell epitopes were identified using the epitope-mapping algorithm, EpiMatrix. These peptide sequences were synthesized and shown in vitro to bind multiple HLA-DR alleles with high affinity, and induce IFNγ responses in healthy donor PBMCs. In the present studies, we establish further correlations between HLA binding and HLA-specific lymphocyte reactions with select epitope clusters. Additionally, we show that the T cell phenotype of C3d-specific reactive T cells is CD4+CD45RO+ memory T cells. Finally, mutation of a single T cell epitope residing within the P28 peptide segment of C3d resulted in significantly diminished adjuvant activity in BALB/c mice. Collectively, these studies support the hypothesis that the paradoxical enhancement of immune responses by C3d in the absence of CD21 is due to internalization and processing of C3d into peptides that activate autoreactive CD4+ T helper cells in the context of HLA class II. |
format | Online Article Text |
id | pubmed-4323994 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
record_format | MEDLINE/PubMed |
spelling | pubmed-43239942015-08-01 C3d adjuvant effects are mediated through the activation of C3d-specific autoreactive T cells De Groot, Anne S. Ross, Ted M. Levitz, Lauren Messitt, Timothy J. Tassone, Ryan Boyle, Christine M. Vincelli, Amber J. Moise, Leonard Martin, William Knopf, Paul M. Immunol Cell Biol Article Complement fragment C3d covalently attached to antigens enhances immune responses, particularly for antigens lacking T cell epitopes. Enhancement has been attributed to receptor cross-linking between complement receptor CR2 (CD21) and polysaccharide antigen to surface IgM on naïve B cells. Paradoxically, C3d has still been shown to increase immune responses in CD21 KO mice, suggesting that an auxiliary activation pathway exists. In prior studies, we demonstrated the CD21-independent C3d adjuvant effect might be due to T cell recognition of C3d T helper epitopes processed and presented by MHC class II on the B cell surface. C3d peptide sequences containing concentrated clusters of putative human C3 T cell epitopes were identified using the epitope-mapping algorithm, EpiMatrix. These peptide sequences were synthesized and shown in vitro to bind multiple HLA-DR alleles with high affinity, and induce IFNγ responses in healthy donor PBMCs. In the present studies, we establish further correlations between HLA binding and HLA-specific lymphocyte reactions with select epitope clusters. Additionally, we show that the T cell phenotype of C3d-specific reactive T cells is CD4+CD45RO+ memory T cells. Finally, mutation of a single T cell epitope residing within the P28 peptide segment of C3d resulted in significantly diminished adjuvant activity in BALB/c mice. Collectively, these studies support the hypothesis that the paradoxical enhancement of immune responses by C3d in the absence of CD21 is due to internalization and processing of C3d into peptides that activate autoreactive CD4+ T helper cells in the context of HLA class II. 2014-11-11 2015-02 /pmc/articles/PMC4323994/ /pubmed/25385064 http://dx.doi.org/10.1038/icb.2014.89 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article De Groot, Anne S. Ross, Ted M. Levitz, Lauren Messitt, Timothy J. Tassone, Ryan Boyle, Christine M. Vincelli, Amber J. Moise, Leonard Martin, William Knopf, Paul M. C3d adjuvant effects are mediated through the activation of C3d-specific autoreactive T cells |
title | C3d adjuvant effects are mediated through the activation of C3d-specific autoreactive T cells |
title_full | C3d adjuvant effects are mediated through the activation of C3d-specific autoreactive T cells |
title_fullStr | C3d adjuvant effects are mediated through the activation of C3d-specific autoreactive T cells |
title_full_unstemmed | C3d adjuvant effects are mediated through the activation of C3d-specific autoreactive T cells |
title_short | C3d adjuvant effects are mediated through the activation of C3d-specific autoreactive T cells |
title_sort | c3d adjuvant effects are mediated through the activation of c3d-specific autoreactive t cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4323994/ https://www.ncbi.nlm.nih.gov/pubmed/25385064 http://dx.doi.org/10.1038/icb.2014.89 |
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