Facilitated By

San Antonio Medical Foundation


UT Health San Antonio

The UT Health San Antonio, with missions of teaching, research and healing, is one of the country’s leading health sciences universities.

Principal Investigator(s)
Xu, Zhenming
Funded by
Research Start Date

B cells as a major source of IL-27 cytokine in antibody responses and anti-viral immunityThis proposal aims to understand a new regulatory role of B lymphocytes, i.e., induction of these cells to produceIL-27 cytokine, underlying molecular mechanisms, and function of B cell-produced IL-27 in the antibody responseand antiviral immunity. As critical immune effectors, B cells integrate innate and adaptive receptor signalstriggered by infections to undergo differentiation for antibody responses, such as class-switching to generatedifferent IgG isotypes. These include IgG2a/IgG2c in the mouse, an IgG isotype with potent anti-viral activitiesand implicated in pathogenic autoantibody response. B cells are also important regulators through productionof cytokines that orchestrate immune responses, such as IL-10, IL-35 and ? as we contend here ? IL-27. Thiscytokine (a heterodimer of IL27p28 and EBI3) functions through its receptor (composed of IL27Ra and gp130)expressed on multiple cell types, including B and T cells. While roles of IL-27 on many T cell subsets have beencomprehensively studied, the impact of IL-27 on B cell differentiation only begins to be understood. As indicatedby others? findings and our preliminary data shown here, IL-27 induces T-bet transcription factor and IgG2aclass-switching in B cells in vitro as well as plays an important role in anti-viral IgG2a responses in vivo. The extensive functional studies of IL-27 contrast the paucity of data on the cellular sources of this cytokine.IL-27 has been considered produced mainly by myeloid cells. However, here we hypothesize that B cells are apreviously unrecognized, and likely major, source of IL-27. The rationale stems from our compelling preliminarydata showing that in vivo Il27p28 and Ebi3 gene expression as well as secretion of the IL27p28/EBI3 heterodimerdepended on B cells. Also, B cells accounted for the majority of IL-27p28 and EBI3 intracellular staining signals.Further, purified human and mouse B cells could be induced to express IL-27 genes and secret IL-27 upon co-stimulation by a TLR ligand and CD154 (CD40 ligand) in vitro. Finally, the synergistic IL-27 induction byTLR/CD40 was augment by IL-21, a hallmark cytokine of T follicular helper (Tfh) cells, in both human and mouseB cells, suggesting an evolutionarily conserved role of IL-21 in a new modality of B cell integrating innate andadaptive signals, namely B cells are primed by TLRs first and then engaged by Tfh cells (Fig. 1).To test our hypothesis, we will address induction of B cell IL-27 production by sequential stimulation, firstwith a TLR ligand and then CD154 and IL-21, and model contacts of TLR-primed B cells and Tfh cells using asupported lipid bilayer system (Aim 1.1). We will also explore mechanisms underlying the TLR/CD40 synergy,with focus on the role of the RIP3 kinase in NF-kB activation (Aim 1.2). Further, we will analyze and characterizeB cells that produce IL-27 at high levels upon immunization or vaccinia virus infection in vivo using Il27p28+/Gfpreporter mice and single-cell transcript analysis (Aim 2.1). Finally, we will address the functional relevance ofB cell production of IL-27 in IgG2a responses and anti-viral immunity using mice with B cell-specific knockoutof Il27p28 or Ebi3 (Aim 2.2). Our findings would advance understanding of new functions of B cells and IL-27.

Collaborative Project
Basic Research
Infectious Disease