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Principal Investigator: Zhenming Xu
Organization: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
Fiscal Year: 2024
Award: $444,851
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY – IL-27-producing B cells in the antibody response
Built on our novel findings that B cells can be induced to express high levels of IL-27 (IL27p28/EBI3 heterodimer),
this proposal will explore molecular and cellular mechanisms underlying the role of IL-27 and IL-27-producing B
cells (B-27 cells) in class-switched antibody (Ab) responses. As we contend, B-27 cells shape the magnitude
and quality of T-dependent Ab responses, including those elicited by viral infections. As we also contend, they
do so as “helper” B cells to enhance the function of their target “effector” B cells, i.e., those responding to antigens
and differentiating into IgG-producing cells. Such class-switched Abs include IgG1, which directly neutralizes
virus, and human IgG3 and mouse IgG2a/IgG2c (IgG2a), which have additional anti-viral effector functions.
Owing to the unique requirement of both innate and adaptive immune receptor signals for their induction, B-27
cells are strategically positioned to mediate the potent effect of TLR ligands in boosting the Ab response.
We hypothesize that B-27 cells are induced in a manner dependent on transcription factor BATF3, and
optimize the Ab response by cooperating with IFNg to promote proliferation, survival and full differentiation of
IgG-producing B cells. This is based on our compelling preliminary data indicating that: (i) as an important
source of IL-27, B cells are induced to produce IL-27 after priming by TLR ligands and then stimulation by Tfh
cell stimuli CD154 and IL-21; (ii) mice with B cell-specific deficiency in Il27p28, Ebi3 or Batf3 are impaired in
IL-27 production and specific IgG2a responses; (iii) IL-27 activates STATs, directs CSR to IgG2a and promotes
survival and plasma cell differentiation in B cells stimulated by CD154 and IL-21 in vitro; and (iv) IL-27 and IFNg
together boost B cell growth and differentiation in vitro, and, conversely, combined IL-27R and IFNgR deficiency
in B cells abrogates specific IgG2a responses and significantly impairs IgG1 responses in vivo.
To test our hypothesis, we will (Aim 1) characterize B-27 cells induced in Tg(Il27p28-Gfp) reporter mice upon
infection by vaccinia virus (VV), which is also used as a vector of a variety of vaccines, or immunization with
conjugated hapten NP-CGG mixed with alum and TLR ligand LPS; and determine the cooperation of B-27 cells
with IFNg in specific IgG responses and underlying effector B cell proliferation, survival, CSR/SHM, plasma cell
and memory B cell differentiation. We will also (Aim 2) address the mechanisms underlying the role of BATF3
in Il27p28 induction by identifying its cis-elements in the Il27p28 locus and partner transcription factors in vitro;
and analyze induction of B cell BATF3 and its impact on B-27 cell generation and Ab responses to VV infection
and NP-CGG/alum/LPS in vivo. Finally, we will (Aim 3) analyze the cooperation of B-cell IL-27R and IFNgR
signals in optimizing effector B cell growth and differentiation in response to VV infection in vivo and stimulation
with CD154 and IL-21 in vitro; and address the underlying mechanisms, focusing on their synergy in regulating
STAT signal outputs and gene expression. By unveiling the mechanisms and function of B-27 cells, our studies
will have a sustained impact on the understanding of IgG responses to viral infections and vaccine development.
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T-Lymphocytes><Infection><Infectious Agent><Interleukin 6 Signal Transducer><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Isotype Switching><Isotype Switchings><Knowledge><LAV-HTLV-III><Ligands><Lymphadenopathy-Associated Virus><Malaria><Measles><Mediating><Medical><Memory B Cell><Memory B-Lymphocyte><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Molecular Interaction><Mumps><Murine><Mus><Nature><Output><Paludism><Plasma Cells><Plasmacytes><Plasmodium Infections><Polio><Poliomyelitis><Position><Positioning Attribute><Poxvirus officinale><Process><Production><Proliferating><Public Health Practice><RNA Expression><Receptor Protein><Receptor Signaling><Recombination><Recording of previous events><Regulation><Reporter><Research><Role><Rubeola><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 vaccine><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 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