PMID- 25385064
OWN - NLM
STAT- MEDLINE
DCOM- 20151214
LR  - 20181113
IS  - 1440-1711 (Electronic)
IS  - 0818-9641 (Print)
IS  - 0818-9641 (Linking)
VI  - 93
IP  - 2
DP  - 2015 Feb
TI  - C3d adjuvant effects are mediated through the activation of C3d-specific 
      autoreactive T cells.
PG  - 189-97
LID - 10.1038/icb.2014.89 [doi]
AB  - 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 naive 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-gamma 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.
FAU - De Groot, Anne S
AU  - De Groot AS
AUID- ORCID: 0000000159111459
AD  - 1] EpiVax Inc., Providence, RI, USA [2] Institute for Immunology and Informatics, 
      Department of Cell and Molecular Biology, University of Rhode Island, Providence, 
      RI, USA.
FAU - Ross, Ted M
AU  - Ross TM
AD  - Vaccine and Gene Therapy Institute of Florida, Port Saint Lucie, FL, USA.
FAU - Levitz, Lauren
AU  - Levitz L
AD  - EpiVax Inc., Providence, RI, USA.
FAU - Messitt, Timothy J
AU  - Messitt TJ
AD  - EpiVax Inc., Providence, RI, USA.
FAU - Tassone, Ryan
AU  - Tassone R
AD  - EpiVax Inc., Providence, RI, USA.
FAU - Boyle, Christine M
AU  - Boyle CM
AD  - EpiVax Inc., Providence, RI, USA.
FAU - Vincelli, Amber J
AU  - Vincelli AJ
AD  - EpiVax Inc., Providence, RI, USA.
FAU - Moise, Leonard
AU  - Moise L
AD  - 1] EpiVax Inc., Providence, RI, USA [2] Institute for Immunology and Informatics, 
      Department of Cell and Molecular Biology, University of Rhode Island, Providence, 
      RI, USA.
FAU - Martin, William
AU  - Martin W
AD  - EpiVax Inc., Providence, RI, USA.
FAU - Knopf, Paul M
AU  - Knopf PM
AD  - EpiVax Inc., Providence, RI, USA.
LA  - eng
GR  - U19 AI082642/AI/NIAID NIH HHS/United States
GR  - NIH U19AI082642/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20141111
PL  - United States
TA  - Immunol Cell Biol
JT  - Immunology and cell biology
JID - 8706300
RN  - 0 (Adjuvants, Immunologic)
RN  - 0 (Epitopes, T-Lymphocyte)
RN  - 0 (Histocompatibility Antigens)
RN  - 0 (Peptides)
RN  - 80295-45-0 (Complement C3d)
RN  - 82115-62-6 (Interferon-gamma)
SB  - IM
MH  - Adjuvants, Immunologic/*metabolism
MH  - Amino Acid Sequence
MH  - Animals
MH  - CD4-Positive T-Lymphocytes/immunology
MH  - Complement C3d/*immunology
MH  - Computer Simulation
MH  - Epitopes, T-Lymphocyte/chemistry/immunology
MH  - Female
MH  - Gene Targeting
MH  - Histocompatibility Antigens/immunology
MH  - Humans
MH  - Immunologic Memory/immunology
MH  - Interferon-gamma/metabolism
MH  - *Lymphocyte Activation/immunology
MH  - Mice, Inbred BALB C
MH  - Molecular Sequence Data
MH  - Mutation
MH  - Peptides/metabolism
MH  - Protein Binding
MH  - T-Lymphocytes/*immunology
MH  - Tissue Donors
PMC - PMC4323994
MID - NIHMS628387
COIS- CONFLICT OF INTEREST These authors recognize the presence of a potential conflict 
      of interest and affirm that the descriptions of experiments represented in this 
      paper are original and unbiased observations.
EDAT- 2014/11/12 06:00
MHDA- 2015/12/15 06:00
PMCR- 2015/08/01
CRDT- 2014/11/12 06:00
PHST- 2012/08/17 00:00 [received]
PHST- 2014/09/12 00:00 [revised]
PHST- 2014/09/12 00:00 [accepted]
PHST- 2014/11/12 06:00 [entrez]
PHST- 2014/11/12 06:00 [pubmed]
PHST- 2015/12/15 06:00 [medline]
PHST- 2015/08/01 00:00 [pmc-release]
AID - icb201489 [pii]
AID - 10.1038/icb.2014.89 [doi]
PST - ppublish
SO  - Immunol Cell Biol. 2015 Feb;93(2):189-97. doi: 10.1038/icb.2014.89. Epub 2014 Nov 
      11.