IL-4–Induced Gene 1: A Negative Immune Checkpoint Controlling B Cell Differentiation and Activation

Abstract

Emerging data highlight the crucial role of enzymes involved in amino acid metabolism in immune cell biology. IL-4-induced gene-1 (IL4I1), a secreted l-phenylalanine oxidase expressed by APCs, has been detected in B cells, yet its immunoregulatory role has only been explored on T cells. In this study, we show that IL4I1 regulates multiple steps in B cell physiology. Indeed, IL4I1 knockout mice exhibit an accelerated B cell egress from the bone marrow, resulting in the accumulation of peripheral follicular B cells. They also present a higher serum level of natural Igs and self-reactive Abs. We also demonstrate that IL4I1 produced by B cells themselves controls the germinal center reaction, plasma cell differentiation, and specific Ab production in response to T dependent Ags, SRBC, and NP-KLH. In vitro, IL4I1-deficient B cells proliferate more efficiently than their wild-type counterparts in response to BCR cross-linking. Moreover, the absence of IL4I1 increases activation of the Syk-Akt-S6kinase signaling pathway and calcium mobilization, and inhibits SHP-1 activity upon BCR engagement, thus supporting that IL4I1 negatively controls BCR-dependent activation. Overall, our study reveals a new perspective on IL4I1 as a key regulator of B cell biology.

Emerging Role of IL-4–Induced Gene 1 as a Prognostic Biomarker Affecting the Local T-Cell Response in Human Cutaneous Melanoma

“…This protective effect is likely due to IL4I1 expression by tumor B cells, the neoplastic counterpart of normal germinal center B cells also overexpressing IL4I1 messengers (Caron et al, 2009). This result is consistent with our recent data showing that IL4I1 finely tunes B-cell physiology (Bod et al, 2018). In contrast, IL4I1 may essentially exert indirect inhibitory functions on the anti-tumor Tcell response in carcinoma, where it is among others expressed by TAM, as confirmed here in melanoma.…”

An Overview of l-Amino Acid Oxidase Functions from Bacteria to Mammals: Focus on the Immunoregulatory Phenylalanine Oxidase IL4I1

“…IL4I1 is also expressed by peripheral blood B cells stimulated by IL-4 and CD40L, which activate the STAT6 and/or NF-κB pathways, respectively [ 60 ], and has been detected in germinal center B cells, i.e., B cells involved in a T-cell-dependent immune response [ 64 , 65 ] ( Figure 3 ). In accordance, we recently demonstrated a key role of IL4I1 in modulating B cell differentiation, particularly at the germinal center stage [ 66 ]. IL4I1 has also been detected in B cell lymphomas originating from the germinal center [ 67 , 68 ], mirroring this natural expression.…”

The transcriptional response of mouse spleen B cells to IL-4: Comparison to the response of human peripheral blood B cells

“…This group includes 15 genes, 14 upregulated and 1 downregulated, that coincided in the present study in mSBC and our previous study in hPBBC. Among the upregulated genes, Cish and Socs1 are protein kinase inhibitors that take part in negative feedback loops to attenuate cytokine signaling [21] ; Nfil3 and Xbp1 are bZIP transcriptional regulators involved in Ig class switching and high-level Ig secretion by plasma cells [22] , [23] ; Vdr (vitamin D3 receptor) controls serum IgE levels [24] ; IL4i1, a L -phenylalanine oxidase, controls BCR-dependent activation [25] ; Dock10, a Rac1 and Cdc42 guanine-nucleotide exchange factor (GEF), is involved in B cell development [16] ; Auh, an RNA-binding hydratase, is involved in mitochondrial protein synthesis [26] ; the Vmp1 gene hosts miR-21 [27] ; and Il4r takes part in a positive feedback loop to amplify IL-4 signaling [4] . Vdr, Cdh1 (E-cadherin), and Slc39a8 were validated by qRTPCR in mSBC ( Fig.…”