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

• Published in: The Journal of immunology (1950) Vol. 200; no. 3; pp. 1027 - 1038
• Main Authors: Bod, Lloyd, Douguet, Laetitia, Auffray, Cédric, Lengagne, Renée, Bekkat, Fériel, Rondeau, Elena, Molinier-Frenkel, Valérie, Castellano, Flavia, Richard, Yolande, Prévost-Blondel, Armelle
• Format: Journal Article
• Language: English
• Published: United States American Association of Immunologists 01.02.2018; Publisher : Baltimore : Williams & Wilkins, c1950-. Latest Publisher : Bethesda, MD : American Association of Immunologists
• Subjects: Activation; Adaptive immunology; AKT protein; Amino Acid Oxidoreductases - genetics; Amino Acid Oxidoreductases - metabolism; Amino acids; Animals; Antigen-presenting cells; B-Lymphocytes - cytology; B-Lymphocytes - immunology; Bone marrow; Calcium; Calcium signalling; Cell activation; Cell differentiation; Cell Differentiation - immunology; Differentiation (biology); Egress; Flavoproteins - genetics; Flavoproteins - metabolism; Immune checkpoint; Immunoglobulins - blood; Immunology; Immunoregulation; Interleukin 4; Life Sciences; Lymphocyte Activation - immunology; Lymphocyte receptors; Lymphocytes; Lymphocytes B; Lymphocytes T; Metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Phenylalanine; Protein Tyrosine Phosphatase, Non-Receptor Type 6 - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Receptors, Antigen, B-Cell - immunology; Ribosomal Protein S6 Kinases - metabolism; Rodents; SHP-1 protein; Signal transduction; Signal Transduction - physiology; Syk Kinase - metabolism; Syk protein
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1601609

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.