![]() ![]() Roles of Gut Microbiome in Systemic Homeostasis of Adaptive Immune Repertoire Gastrointestinal Tract as a Key Site for Systemic Immune Modulation In this article, we highlight the recent advancement in high-throughput immune repertoire analysis by next-generation sequencing (NGS) and its possible application in future studies to elucidate previously unrecognized mechanisms of immune modulation by gut microbiota and oral nutrition. For instance, several groups have reported pivotal observations that alloimmune-mediated graft-versus-host reactions in the setting of hematopoietic cell transplantation and immune responses against malignant neoplasms triggered by immune checkpoint inhibition are associated with the abundance of distinct members of intestinal commensal flora ( 4– 8). Furthermore, until recently, there had been no available technologies that comprehensively identify each of TCR and BCR/Ig clonotypes constituting the whole adaptive immune cell repertoire.ĭuring the past few decades, accumulative lines of evidence have indicated that the host microbiome and nutrients not only play key roles for balancing the host immunity in health and disease but have a tremendous influence on the generation and shaping of immune cell repertoire ( 2, 3). However, the underlying mechanism by which these repertoires are ontogenetically developed and shaped is largely unknown. It is well-characterized that such huge diversity of antigen-specific receptors is created through somatic rearrangement of variable (V), diversity (D), and joining (J) (or V and J) gene segments located in TCR- or BCR/Ig-encoding loci and the concomitant incorporation of random nucleotide insertions and deletions. At the individual level, the estimated number of TCR and BCR/Ig clonotypes is from a few thousands to more than billions depending on the species of animal, which is believed to form the basis of the host ability to cope with innumerable immunologic threats. At the single-cell level, these cells express a single type of unique antigen-specific receptors: T-cell receptor (TCR) for T cells and B-cell receptor/immunoglobulin (BCR/Ig) for B cells that define a phenotypic clone or a clonotype of these immune cells. In this paradigm of the “adaptive” immune system, it is firmly believed that pre-existing repertoire of two types of lymphohematopoietic cells, classic T cells and B cells, predominantly determine the mode and pattern of immune responses in a given individual. The jawed vertebrates have evolutionally acquired a unique immune system consisted of effector and regulator cells that can effectively respond or establish tolerance to millions of endoneous and environmental antigens in an epitope-specific manner ( 1). Accumulation of such knowledge will lead to the development of effective ways for personalized immune modulation through deeper understanding of the mechanisms by which the intestinal environment affects our immune ecosystem. Although there are still unsolved caveats, this emerging technology combined with single-cell transcriptomics/proteomics provides a critical tool to unveil the previously unrecognized principle of host–microbiome immune homeostasis. In this article, we aim to discuss the possible application of high-throughput immune receptor sequencing in the field of nutritional and intestinal immunology. Sophisticated immuno-bioinformatic analyses by use of this innovative methodology have been already implemented in clinical development of antibody engineering, vaccine design, and cellular immunotherapy. Over the past several years, high-throughput next-generation sequencing has been developed as a powerful tool to profile T- and B-cell receptor repertoires in a given individual at the single-cell level. Acquired immunity against various microorganisms including host microbiome is principally founded on T cell and B cell populations, each of which expresses antigen-specific receptors that define a unique clonotype. Although advances in modern immunology have revealed a role of many unique immune cell subsets, technologies that enable us to capture the whole landscape of immune responses against specific antigens have been not available to date. The human immune system is a fine network consisted of the innumerable numbers of functional cells that balance the immunity and tolerance against various endogenous and environmental challenges. 4Department of Rheumatology and Clinical Immunology, Clinical Research Center for Rheumatology and Allergy, National Hospital Organization Sagamihara Hospital, Sagamihara, Japan.2Repertoire Genesis Incorporation, Ibaraki, Japan. ![]() ![]() 1Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine (RIRBM), Hiroshima University, Hiroshima, Japan.Tatsuo Ichinohe 1* † Takahiko Miyama 1† Takakazu Kawase 1 Yasuko Honjo 1 Kazutaka Kitaura 2 Hiroyuki Sato 2 Tadasu Shin-I 3 Ryuji Suzuki 2,4 ![]()
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