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CHaPter 14 The Microbiota in Immunity and Inflammation 211

Small intestine Large intestine

Lumen

Outer
mucous layer

SlgA

AMPs Inner
mucous layer

Apical
IECs
Entero- Paneth Goblet Basolateral
cyte cell cell
IL-22R
plgR Tight junctions
IL-22
Lamina propria SlgA-producing
plasma cell
LTi cell NK-22
FIG 14.4 Active Barrier Functions of the Intestinal Epithelium. The intestinal epithelium comprises
a single layer of polarized columnar epithelial cells (IECs), sealed by tight junctions. Specialized
cells known as goblet cells secrete mucins that form a bilayered mucus sheath, which maintains
separation between the luminal bacteria and the epithelium. The thicker inner mucus layer is
sparsely populated with bacteria, whereas the outer layer is more loosely structured and contains
≈10-fold more bacteria. Paneth cells within the epithelium secrete defensins which, along with
epithelial-derived antimicrobial peptides, further help with bacterial containment. Epithelial cells
also transport antibodies into the lumen and transmit cytokine signals that help maintain barrier
integrity.

to spontaneous multiorgan autoimmune disease very early in
Invariant Natural Killer T Cells life. Commencing in the first few days of life, FOXP3 Tregs are
+
A unique subset of thymus-derived cells, invariant NK T (iNKT) exported from the thymus to seed every lymphoid and nonlym-
cells (Chapter 17) express an invariant T-cell receptor (TCR) phoid tissue. Most Tregs in the intestine express Foxp3, and
(Chapter 4) that recognizes lipid antigens presented by the most of these coexpress IL-10, TGF-β, and IL-35. However,
−
nonclassic MHC class I molecule CD1d (Chapter 5). iNKT cells other FOXP3 subsets also exist including IL-10-producing
are essential for the ulcerative colitis–like phenotype that develops Tr1 cells, as well as the CD4CD8αα T cells in the human
in experimental mice treated with the chemical compound lamina propria. 15
oxazolone. Studies on the role of the microbiota in iNKT cell Commensal-specific Foxp3-expressing Tregs in the intestinal
expansion and function provided an elaborate example of the lamina propria are potentially a mixture of thymic-derived Tregs
16
how early postnatal colonization can profoundly impact the (tTregs) and peripherally induced Tregs (pTregs). In support
maturation and long-term function of the immune system. of the latter, mice deficient in their ability to generate extrathymic
+
Germ-free mice harbor increased numbers of iNKT cells in both Foxp3 Tregs spontaneously develop intestinal pathology late in
the colon and the lung, and correspondingly demonstrate life. Colonization of germ-free mice with a benign cocktail of
increased severity of experimental colitis and asthma. The disease eight commensal microbes, collectively referred to as altered
phenotype can be reduced to that of conventionally raised mice Schaedler flora, is sufficient to induce expansion and accumulation
+
if germ-free mice are colonized with commensals in the neonatal of Foxp3 cells in the large intestine, approaching the levels seen
period, but not during adulthood. 14 in conventionally raised mice. However, a case has been made
for the ability of specific bacteria and/or bacterial components
Regulatory T Cells to uniquely promote Treg induction. For example, a cocktail of
Regulatory T cells (Tregs) (Chapter 18) are crucial to the estab 46 mouse Clostridium strains potently induced expansion of
+
17
lishment and maintenance of immune homeostasis. Mice or colonic Foxp3 cells. This cocktail, which has since been reduced
humans with absent or defective expression of the signature to 17 strains derived from a single human donor, and recapitulates
Treg transcription factor Foxp3 (FOXP3 in humans) succumb the phenotype in germ-free mice.