T cell control of the gut IgA response against commensal bacteria.

The immunoglobulin A (IgA) is produced to defend mucosal surfaces from environmental organisms, but host defenses against the very heavy load of intestinal commensal microorganisms are poorly understood. The IgA against intestinal commensal bacterial antigens was analyzed; it was not simply “natural antibody” but was specifically induced and responded to antigenic changes within an established gut flora. In contrast to IgA responses against exotoxins, a significant proportion of this specific anti-commensal IgA induction was through a pathway that was independent of T cell help and of follicular lymphoid tissue organization, which may reflect an evolutionarily primitive form of specific immune defense. Comment In humans and most experimental mammals the gut lamina propria (LP) is the site of prodigious synthesis of the IgA isotype of immunoglobulin (Ig) and its secretion into the lumen. The major part of total Ig synthesis occurs here, leading to questions concerning the possible specific and non-specific stimuli of its production and the usefulness of this product to the host. Clearly, this typically continuous output of IgA is not constitutive as axenic (germ free (GF)) and newborn humans and other mammals display few secretory IgA plasmablasts in gut LP and minimal levels of secreted IgA in their gut lumen. 2 In some way, colonisation with members of the normal gut microbiota seem to initiate the development and chronic activity of certain elements of the humoral mucosal immune system. 4 This IgA consists of specific antibodies identifiably reactive with colonising bacteria, as well as of large quantities of IgA that cannot be shown to have been stimulated by or be reactive with particular antigens (Ags) present in food or microbes—so called “natural” IgA. In the mouse, the apparent duality of the IgA response might be explained by a diVerence in origin: firstly, conventional B cells (also called B2 cells) are specifically stimulated by microbial Ags and benefit from cognate interaction with Ag specific CD4 T cells. They are clonally expanded in germinal centre reactions (GCR) in Peyer’s patches (PP) and mesenteric lymph nodes, and benefit from the positive selection process occurring in GCR leading to aYnity maturation that results in specific IgA antibodies. 6 Secondly, a separate lineage of B cells, termed B1 cells, can be observed in the mouse. These cells, originally defined by expression of the surface marker CD5 and high expression of IgM, arise early in ontogeny, reside in the peritoneal and pleural cavity, and display receptor specificities mainly different from those of B2 cells. B1 cells as well as B2 cells require colonisation of the gut by microbes to stimulate development into gut IgA secreting cells but they do not participate in cognate interaction with CD4 T cells or in GCR with consequent aYnity maturation. B1 cells require or benefit from exogenous cytokines such as interleukin (IL)-5, IL-6, and IL-10, and are thought to be the main source of “natural” IgA. A recent paper by MacPherson and colleagues put forward new ideas about the natural development of this gut IgA system. In their paper they provided evidence to show that much of this development and functioning is independent of T lymphocytes or their lymphokines, thereby minimising “bystander” contributions of T cells mediated by their lymphokines (see Wetzel). Furthermore, in this paper it was claimed that the contributions to IgA in the gut are Ag driven and specifically selected, mainly by microbial and food Ags, thus neglecting the supposed critical role of microbial polyclonal stimuli such as lipopolysaccharide, in contributing to the generation of the B cell elements that function in the gut. Finally, evidence is shown that the responsible B cell subset for this “T cell independent” IgA production is well represented in neonatal and adult mice by B1 cells. The basic phenomenon—the apparently excessive production of IgA in the gut—entreats the discovery of a rationale in terms of benefit to the host. However, calibration of the quantitative importance of the general mechanisms proposed by the two hypotheses—reasonably supposing they may both be somewhat operative—is critical in discerning: (1) whether neonates may be expected to respond to various orally encountered polyvalent microbial Ags; and (2) whether the peculiar evolution of an individual’s gut microbiota (and exposure to particular food Ags) may distort the eVective B cell repertoire available on encounter with any given frank or opportunistic pathogenic microbe via the gut. In the paper by MacPherson and colleagues, increased production of gut IgA, some of which reacted with Ags from commensal bacteria, was investigated using specific pathogen free (SPF) mice with rather low background levels of IgA relative to conventionally reared mice. SPF mice were then presumably “super colonised” by oral introduction of novel enteric microbes, some of which carried plasmids encoding distinct protein Ags. Generally, IgA secreting cells in gut LP increased approximately threefold and antibodies specific for particular bacterial Ags were detected by western blotting and Ag specific quantitative ELISA assays of gut washings. Similar findings have been made over the past decades using GF mice monoassociated with a particular enteric microbe or infected with an enteric virus, and evidence for GCR in PPs has supported the T cell dependence of at least part of the response. 12 13 The novel findings and interpretations by MacPherson and colleagues are that SPF T cell receptor (TCR) knockout (KO) (TCR; â(−/−), ä(−/−)) mice display the same overall Gut 2001;48:762–764 762 www.gutjnl.com group.bmj.com on June 26, 2017 Published by http://gut.bmj.com/ Downloaded from