Neddylation contributes to CD4+ T cell-mediated protective immunity against blood-stage Plasmodium infection

Abstract

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.

Neddylation: a novel modulator of the tumor microenvironment

“…Moreover, neddylation inhibition leads to impaired antigen-driven cytokine production (e.g. IFN-γ, IL-2 and IL-4), which is required for efficient Th1 and Th2 differentiation [70], demonstrating a potent positive function of neddylation pathway in T-cell activation [69, 71]. Consistently, deletion of RBX2 significantly decreased T-cell activation and T-effector cytokine release upon in vitro allogeneic stimulation [72].…”

“…Interestingly, neddylation pathway seems to directly regulate Shc to facilitate the formation of a ZAP70-Shc-Grb2 signaling complex and affect downstream Erk activation [69, 74]. Subsequently, Cheng et al reported that neddylation pathway is required for supporting various aspects of CD4 + T-cell functions, through B cell lymphoma-2 (Bcl-2)-mediated suppression of the mitochondria-dependent apoptosis [71]. Moreover, neddylation contributes to follicular Th cells differentiation, probably via augmenting the activity of ubiquitin ligase activity Itch by a mono-neddylation process and subsequent proteasomal degradation of FOXO1, a transcription factor implicated in multiple aspects of T-cell functions [71, 75].…”

“…Subsequently, Cheng et al reported that neddylation pathway is required for supporting various aspects of CD4 + T-cell functions, through B cell lymphoma-2 (Bcl-2)-mediated suppression of the mitochondria-dependent apoptosis [71]. Moreover, neddylation contributes to follicular Th cells differentiation, probably via augmenting the activity of ubiquitin ligase activity Itch by a mono-neddylation process and subsequent proteasomal degradation of FOXO1, a transcription factor implicated in multiple aspects of T-cell functions [71, 75]. Collectively, these findings indicate that inhibition of neddylation pathway acts as crucial modulators of T cells activation and anti-tumor immune response.…”

Neddylation Facilitates the Antiviral Response in Zebrafish

“…The role of protein neddylation in immunological regulation has received increasing attentions (12–14). The inhibition of neddylation leads to the suppression of LPS-induced pro-inflammatory cytokine production in macrophage cells (15).…”

“…Recently, it has been shown that blocking the neddylation pathway suppresses influenza virus replication and the pro-inflammatory response (20). Finally, neddylation enhances CD4 + T cell-mediated protective immunity against–blood stage Plasmodium infection (12). Interestingly, MLN4924, an inhibitor of NAE, inhibits TLR3/4 and retinoic acid-inducible gene I-induced IFN-β expression by preventing IRF3 binding to the IFN-β promoter, with a neddylation-independent manner (21).…”