How MHCII signaling promotes benign host-microbiota interactions

Introduction: Major histocompatibility complex class II molecules and the microbiotaThe major histocompatibility complex (MHC) is a hyper-polymorphic gene-dense region found on Chromosome 6 in humans (the human MHC is termed the HLA for "human leukocyte antigen").The "hyper"-polymorphic nature of this region stems from the extreme allelic diversity found within classical Class I and class II MHC (MHCII) genes [1] (Fig 1A).MHCII genes encode cell-surface glycoproteins that bind extracellularly derived peptide antigens and present them on the surface of antigen presenting cells (APCs; conventionally, dendritic cells [DCs], macrophages, and B cells).MHCII:peptide complexes engage T cell receptors (TCRs) and CD4 co-receptors which facilitates cognate interactions between CD4 + T cells and APCs.In humans, MHCII deficiency (also known as "bare lymphocyte syndrome type II") is caused by loss-of-function mutations in genes that drive MHCII surface expression on APCs [2].The primary immunological features of MHCII deficiency include severe deficits in peripheral CD4 + T cells and circulating antibody titers.Severe recurrent infection, especially of the gastrointestinal tract, is the major complication associated with MHCII deficiency in humans.These individuals have an extremely poor prognosis and often succumb to infectious disease in their childhood [3,4].Therefore, MHCII-mediated immune responses directed against gastrointestinal microbes is a crucial component of health.In addition to promoting resistance to pathogenic microbes, MHCII is also emerging as an important pathway regulating interactions between vertebrate hosts and the bacterial community that persistently colonizes the gastrointestinal tract (collectively termed the microbiota).Recent work in MHCII conditional knockout mice has revealed conventional and unconventional roles of MHCII-mediated antigen presentation in promoting benign host-microbiota interactions, and emerging data support that polymorphism at MHCII loci drives variability in microbiota-dependent disease phenotypes. How MHCII promotes benign host-microbiota symbiosisImmunoglobulin A (IgA) is the most abundantly secreted antibody in the gut.T cell dependent (TD) and T cell independent (TiD) B cell maturation contributes to the pool of IgAsecreting plasma cells in the gut.The balance between TiD and TD IgA responses is different between inbred mouse strains suggesting that immunogenetic variation may play an important role in this balance [5].Using a CD3ε -/-adoptive transfer mouse model, Kawamoto and colleagues were the first to explicitly demonstrate that TD IgA responses may have a significant