The ubiquitin ligase Peli1 inhibits ICOS and thereby Tfh-mediated immunity

Abstract

T follicular helper (Tfh) cells are crucial for regulating autoimmune inflammation and protective immunity against viral infection. However, the molecular mechanism controlling Tfh cell differentiation is poorly understood. Here, through two mixed bone marrow chimeric experiments, we identified Peli1, a T cell-enriched E3 ubiquitin ligase, as an intrinsic regulator that inhibits Tfh cell differentiation. Peli1 deficiency significantly promoted c-Rel-mediated inducible T-cell costimulator (ICOS) expression, and PELI1 mRNA expression was negatively associated with ICOS expression on human CD4+ T cells. Mechanistically, increased ICOS expression on Peli1-KO CD4+ T cells enhanced the activation of PI3K-AKT signaling and thus suppressed the expression of Klf2, a transcription factor that inhibits Tfh differentiation. Therefore, reconstitution of Klf2 abolished the differences in Tfh differentiation and germinal center reaction between WT and Peli1-KO cells. As a consequence, Peli1-deficient CD4+ T cells promoted lupus-like autoimmunity but protected against H1N1 influenza virus infection in mouse models. Collectively, our findings established Peli1 as a critical negative regulator of Tfh differentiation and indicated that targeting Peli1 may have beneficial therapeutic effects in Tfh-related autoimmunity or infectious diseases.

Goliath induces inflammation in obese mice by linking fatty acid β‐oxidation to glycolysis

“…To examine whether CD4 + T cells from obese mice have enhanced ability to induce inflammation, we adoptively transferred the same amount of lean or obese mice (C57BL/6 background)‐derived CD45.2 + CD4 + T cells into BM12/SJL mice (CD45.1 + CD45.2 + ) to induce an inflammation model, which will exclude the influence of in vivo complex microenvironment of obesity mice. Since the BM12 mice differ from C57BL/6 mice by three amino acid substitutions in the β‐chain of the MHC class II molecule I‐A, this adoptive transfer will induce the expansion of donor‐derived T follicular helper (Tfh) and recipient‐derived germinal center (GC) B cells and plasma cells, resulting in the production of antinuclear antibody and IgG deposits in the kidneys of recipient mice, thereby leading to the induction of chronic GVHD with symptoms closely resembling lupus‐like disease (Wang et al , 2016; Liu et al , 2018; Huang et al , 2021). As expected, the percentages of lean‐ and obese‐derived CD4 + T cells into regulatory T (Treg), Th1, Th17, and Th2 cells in the recipient mice were comparable, while the frequencies and absolute numbers of the transferred CD45.2 + Tfh cells, recipient GC B and plasma cells were greatly increased in obese CD4 + T cells group.…”

HNF4α ubiquitination mediated by Peli1 impairs FAO and accelerates pressure overload-induced myocardial hypertrophy

“…Peli1, an E3 ubiquitin ligase, has been primarily associated with TLR signaling and various intracellular inflammatory and innate immune signaling pathways [ 43 – 46 ]. However, the non-inflammatory regulatory role of Peli1 in cell signaling remains incompletely characterized.…”

E3-ubiquitin ligases and recent progress in osteoimmunology

“…Additionally, these genetic studies have partially uncovered the association between E3-ligases and inflammatory human disorders. Further studies in humans are thus required in order to provide new genetic evidence of other ligases, including NEDD4-2 (75), HUWE1 (76), c-MIR (77), Cullin3 (78), FBW7 (79-82), MARCH1 (83-88), MURF1 (89-92), RNF90 (93)(94)(95), SAG (96), Hrd1 (97), Peli1 (98,99), TRIM (100-102) and MYCBP2 (103), that have been shown to be associated with the osteoimmune system in previous in vitro and in vivo mouse studies.…”