The immune system in the mucosa has to distinguish between potential pathogens and harmless antigens, generating strong effector responses to pathogens but remaining unresponsive to foods and commensals. Food proteins induce an active form of immunological tolerance in the systemic and mucosal immune systems; this tolerance may be mediated by regulatory T cells producing IL-10 and/or TGF-β. Commensal bacteria are also recognized by the immune system, but this is limited to the mucosa and its draining lymphoid tissues because commensal antigens are presented to T cells by semi-mature dendritic cells that migrate from the intestinal wall to draining mesenteric lymph nodes. This results in active mucosal tolerance and the production of local IgA antibodies that restrict colonization by the microorganisms, but ‘ignorance’ of these antigens by the systemic immune system. Because commensal bacteria have many beneficial effects for the host, these immunoregulatory processes are important in allowing the bacteria to coexist with the immune system. When the normal regulatory processes break down, local dendritic cells become fully activated and induce differentiation of naive T cells into effector T cells in the mesenteric lymph node. This is important for protective immunity against pathogens, but when it occurs under the wrong circumstances, it can lead to inflammatory diseases such as Crohn’s disease or celiac disease. As a consequence of these competing, but interacting, needs of the immune response, the intestine normally has the appearance of physiological inflammation, which helps maintain normal function of the gut and immune system. This process is driven mostly by the need to control the intestinal microbiota without eliminating it completely or causing damaging inflammation, and results in the coordinated production of IgA, activation of regulatory and effector T cells, and several innate immune responses. Abnormalities in the host response can alter the composition and behavior of the microbiota, while changes in the microbiota can also influence the development and outcome of many diseases outside the intestine.
Summary to Chapter 12.
The mucosal immune system is a large and complex apparatus that has a crucial role in health, not just by protecting physiologically vital organs but also by helping to regulate the tone of the entire immune system and prevent disease. The peripheral lymphoid organs focused on by most immunologists may be a recent specialization of an original template that evolved in mucosal tissues. The mucosal surfaces of the body are highly vulnerable to infection
Fig. 12.24 T cells with the potential to produce inflammation in response to commensal bacteria are present in normal animals, but are controlled by regulatory T cells. Transfer of unseparated CD4+ T cells from a normal mouse into an immunodeficient mouse, such as one lacking the rag gene (rag –/–), will lead to reconstitution of the CD4+ T‑cell compartment. However if ‘naive’ CD4+ T cells (CD4+CD45RBhi) are purified and transferred, the host mice develop severe inflammation of the colon. This can be prevented by co‑transferring the CD4+CD25+ FoxP3+ T cells that were removed during the purification of the naive CD4+ T‑cell population. The effects of these regulatory T cells are blocked by neutralizing TGF‑β in vivo and are also dependent on IL‑10. The intestinal inflammation caused by naive CD4+ T cells requires the presence of the microbiota, as it is prevented in germ‑free mice, or by treatment with antibiotics. These experiments demonstrate that some CD4+ T cells in normal animals are capable of provoking inflammatory responses against the intestinal microbiota, but that these are normally held in check by regulatory T cells. Micrographs from Powrie, F., et al.: J. Exp Med. 1996, 183:2669–2674.