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C3d adjuvant effects are mediated through the activation of C3d‐specific autoreactive T cells
Author(s) -
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
Publication year - 2015
Publication title -
immunology and cell biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.999
H-Index - 104
eISSN - 1440-1711
pISSN - 0818-9641
DOI - 10.1038/icb.2014.89
Subject(s) - epitope , antigen , immune system , major histocompatibility complex , biology , t cell , antigen presenting cell , adjuvant , complement system , cytotoxic t cell , immunology , t cell receptor , microbiology and biotechnology , in vitro , biochemistry
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 knockout 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 major histocompatibility complex 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 human leukocyte antigen (HLA)‐DR alleles with high affinity, and induce interferon‐γ responses in healthy donor peripheral blood mononuclear cells. In the present studies, we establish further correlations between HLA binding and HLA‐specific lymphocyte reactions with select epitope clusters. In addition, 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.