Poly‐ADP‐ribosyl polymerase‐14 promotes T helper 17 and follicular T helper development

Abstract

SummaryTranscription factors are critical determinants of T helper cell fate and require a variety of co-factors to activate gene expression. We previously identified the ADP ribosyl-transferase poly-ADP-ribosyl polymerase 14 (PARP-14) as a co-factor of signal transducer and activator of transcription (STAT) 6 that is important in B-cell and T-cell responses to interleukin-4, particularly in the differentiation of T helper type 2 (Th2) cells. However, whether PARP-14 functions during the development of other T helper subsets is not known. In this report we demonstrate that PARP-14 is highly expressed in Th17 cells, and that PARP-14 deficiency and pharmacological blockade of PARP activity result in diminished Th17 differentiation in vitro and in a model of allergic airway inflammation. We further show that PARP-14 is expressed in T follicular helper (Tfh) cells and Tfh cell development is impaired in PARP-14-deficient mice following immunization with sheep red blood cells or inactivated influenza virus. Decreases in Th17 and Tfh development are correlated with diminished phospho-STAT3 and decreased expression of the interleukin-6 receptor a-chain in T cells. Together, these studies demonstrate that PARP-14 regulates multiple cytokine responses during inflammatory immunity.

The impact of PARPs and ADP-ribosylation on inflammation and host–pathogen interactions

“…regulating STAT6-dependent Gata3 expression and that PARP14-deficient mice show reduced symptoms of allergic airway disease Riley et al 2013). PARP14 enhances STAT3-dependent Th17 differentiation (Mehrotra et al 2015). PARP14 is also implicated in immunoglobulin class switching in B cells by enhancing the IL-4 and STAT6 signal, which produces the IgE isotype, a major factor in allergic hypersensitivity (Mehrotra et al 2011).…”

Poly(ADP-Ribose) Polymerases in Host-Pathogen Interactions, Inflammation, and Immunity

“…PARP14 regulates the IL-4-mediated proliferation and survival of B cells and is highly expressed in Th17 cells. Inhibition of this protein results in reduced Th17 cell differentiation in a model of allergic airway inflammation (261)(262)(263). PARP14 influences the class distribution and affinity repertoire of antibodies in mice and is involved in helper T-cell development (261,264).…”

Poly‐ADP ribose polymerase‐14 limits severity of allergic skin disease

“…Interleukin‐17 might be another important effector cytokine. In vitro , Parp14 −/− Th17 cells had significantly reduced frequency of IL‐17A + cells and in vivo , in a model of allergic airway disease, Parp14 −/− mice had decreased numbers of IL‐17A‐producing CD4 + cells and a reduced concentration of IL‐17A from antigen‐stimulated splenocytes . However, in Stat6VT× Parp14 −/− mice, we observed an overall increase in IL‐17A‐producing CD4 + cells.…”

“…PARP14 promotes differentiation of Th cells to a Th2 phenotype, promotes Th17 development and has no effect on Th1 differentiation and IFN‐ γ production . To study how the absence of PARP14 affects cytokine production in Stat6VT mice, we analysed CD4 T‐cell production of IL‐4, IL‐13, IFN‐ γ and IL‐17A by intracellular cytokine staining and ELISA (Fig.…”

“…The cells were then fixed with 4% formaldehyde for 10 min at room temperature, permeabilized with permeabilization buffer (BD Biosciences, San Jose, CA) and with fluorochrome‐conjugated antibodies for IL‐4, IL‐13, interferon‐ γ (IFN‐ γ ) and IL‐17A. Stimulation and antibodies were used as previously described …”