Tissue adaptation: Implications for gut immunity and tolerance

Abstract

Tissue adaptation is an intrinsic component of immune cell development, influencing both resistance to pathogens and tolerance. Chronically stimulated surfaces of the body, in particular the gut mucosa, are the major sites where immune cells traffic and reside. Their adaptation to these environments requires constant discrimination between natural stimulation coming from harmless microbiota and food, and pathogens that need to be cleared. This review will focus on the adaptation of lymphocytes to the gut mucosa, a highly specialized environment that can help us understand the plasticity of leukocytes arriving at various tissue sites and how tissue-related factors operate to shape immune cell fate and function.

Figure 1.

T cell plasticity during lineage commitment. Lymphoid precursors exit the bone marrow and migrate to the thymus, where they differentiate into mature T cells. Rag1/2-dependent TCR rearrangement gives rise to TCRγδ and TCRαβ lineages, while MHC restriction and TCR strength leads to CD4 or CD8 commitment of the TCRαβ lineage in a Runx3- and ThPOK-dependent manner. Mature CD4 and CD8 T cells exit the thymus and receive further activation and differentiation signals in secondary lymphoid organs and nonlymphoid tissues. Each commitment step is generally associated with loss of cell plasticity, although migration to particular tissue or effector sites may allow reacquisition of various levels of plasticity, depending on the target tissue, contexts, and intratissue microenvironments.

Figure 2.

Intestinal microenvironments and niches. The intestine is exposed to constant luminal stimulation and harbors a dense and very diverse set of immune cells. Different layers of the intestinal tissue and regions along the gastrointestinal tract are subjected to particular stimuli, which are coupled with site-specific adaptation of immune cell subsets. The figure depicts the main characteristics of the intestinal layers, proximal-distal regions and immune cells populations exposed to chronic stimulation by dietary and microbial antigens. Although stimulation by dietary antigens or metabolites decreases from proximal to distal intestine, microbial stimulation follows the opposite direction. An approximate illustration of the changes in abundance of each cell type per intestinal region is shown on the bottom.