Open AccessNeddylation contributes to CD4+ T cell-mediated protective immunity against blood-stage Plasmodium infection
Author(s) -
Qianqian Cheng,
Jian Liu,
Yujun Pei,
Yaolin Zhang,
Dawang Zhou,
Weiqing Pan,
Jiyan Zhang
Publication year - 2018
Publication title -
plos pathogens
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.719
H-Index - 206
eISSN - 1553-7374
pISSN - 1553-7366
DOI - 10.1371/journal.ppat.1007440
Subject(s) - neddylation , biology , nedd8 , plasmodium yoelii , germinal center , microbiology and biotechnology , immunity , ubiquitin , t cell , immunology , ubiquitin ligase , immune system , b cell , parasitemia , plasmodium falciparum , antibody , malaria , biochemistry , gene
CD4 + T cells play predominant roles in protective immunity against blood-stage Plasmodium infection, both for IFN-γ-dependent effector mechanisms and providing B cell helper signals. Neddylation, an ubiquitination-like process triggered by covalent conjugation of NEDD8 to specific targets, has emerged as a potential regulator of T cell activities to TCR engagement. However, its contribution to T cell-mediated immunity to blood-stage malaria remains unclear. Here using an experimental model induced by Plasmodium yoelii 17XNL, and conditional knockout mice with T cell-specific deficiency of crucial components of neddylation pathway, we demonstrate activation of neddylation in T cells during blood-stage Plasmodium infection is essential for parasite control and host survival. Mechanistically, we show that apart from promoting CD4 + T cell activation, proliferation, and development of protective T helper 1 (Th1) cell response as suggested previously, neddylation is also required for supporting CD4 + T cell survival, mainly through B-cell lymphoma-2 (Bcl-2) mediated suppression of the mitochondria-dependent apoptosis. Furthermore, we provide evidence that neddylation contributes to follicular helper T (Tfh) cell differentiation, probably via augmenting the ubiquitin ligase Itch activity and proteasomal degradation of FoxO1, thereby facilitating germinal center (GC) formation and parasite-specific antibody production. This study identifies neddylation as a positive regulator of anti- Plasmodium immunity and provides insight into an involvement of such pathway in host resistance to infectious diseases.