Tissue Tregs

Abstract

The immune system is responsible for defending an organism against the myriad of microbial invaders it constantly confronts. It has become increasingly clear that the immune system has a second major function: the maintenance of organismal homeostasis. Foxp3(+)CD4(+) regulatory T cells (Tregs) are important contributors to both of these critical activities, defense being the primary purview of Tregs circulating through lymphoid organs, and homeostasis ensured mainly by their counterparts residing in parenchymal tissues. This review focuses on so-called tissue Tregs. We first survey existing information on the phenotype, function, sustaining factors, and human equivalents of the three best-characterized tissue-Treg populations-those operating in visceral adipose tissue, skeletal muscle, and the colonic lamina propria. We then attempt to distill general principles from this body of work-as concerns the provenance, local adaptation, molecular sustenance, and targets of action of tissue Tregs, in particular.

Keywords: adipose tissue; metabolism; microbiota; mucosal immunology; skeletal muscle; tissue repair.

Figure 1

Visceral adipose tissue. Schematic representation of a transverse section of epididymal fat from a lean adult B6 mouse. Abbreviations: DC, dendritic cell; ILC2, type 2 innate lymphoid cell; MF, macrophage; Teff, effector T cell (either Foxp3⁻CD4⁺ or CD8⁺); Treg, regulatory T cell.

Figure 2

Cytokines differentially expressed in tissue Tregs. K-means clustering (K = 4) of cytokine transcripts more than twofold upregulated in Tregs from at least one of the indicated parenchymal tissues vis-à-vis their lymphoid-organ Treg counterparts. Abbreviations: V, VAT (epididymal fat) from 20- to 25-week-old B6 mice; M, skeletal muscle 2 weeks after cardiotoxin-induced injury of young adult B6 mice; CR⁺ and CR⁻, RORγt⁺ and RORγt⁻ Treg subpopulations from colonic lamina propria of young adult B6 mice; P, pancreas from 10-week-old NOD mice. Bar refers to fold-change differences on a log2 scale.

Figure 3

Schematic representation of bundles of skeletal muscle fibers (a) and of a transverse section of one bundle (b). Representative of uninjured gastrocnemius muscle from a young adult mouse. Abbreviations: DC, dendritic cell; MF, macrophage; Teff, effector T cell (either Foxp3⁻CD4⁺ or CD8⁺); Treg, regulatory T cell.

Figure 4

Schematic representation of a transverse section of the colon of a young adult mouse. The DC projection is sampling microbes. Abbreviations: DC, dendritic cell; IEL, intraepithelial lymphocyte; ILC, innate lymphoid cell; MF, macrophage; Teff, effector T cell (either Foxp3⁻CD4⁺ or CD8⁺); Treg, regulatory T cell.

Figure 5

Transcription factors differentially expressed in tissue Tregs. K-means unsupervised clustering (K = 5) of transcription factor gene transcripts more than twofold upregulated in Tregs from at least one of the indicated parenchymal tissues vis-à-vis their lymphoid-organ Treg counterparts. Abbreviations: V, VAT (epididymal fat) from 20- to 25-week-old B6 mice; M, skeletal muscle 2 weeks after cardiotoxin-induced injury of young adult B6 mice; CR⁺ and CR⁻, RORγt⁺ and RORγt⁻ Treg subpopulations from colonic lamina propria of young adult B6 mice; P, pancreas from 10-week-old NOD mice. Bar refers to fold-change differences on a log2 scale.