Abstract
T regulatory (Treg) cells play vital roles in modulating immunity and tissue homeostasis. Their actions depend on TCR recognition of peptide-MHC molecules; yet the degree of peptide specificity of Treg-cell function, and whether Treg ligands can be used to manipulate Treg cell biology are unknown. Here, we developed an Ab-peptide library that enabled unbiased screening of peptides recognized by a bona fide murine Treg cell clone isolated from the visceral adipose tissue (VAT), and identified surrogate agonist peptides, with differing affinities and signaling potencies. The VAT-Treg cells expanded in vivo by one of the surrogate agonists preserved the typical VAT-Treg transcriptional programs. Immunization with this surrogate, especially when coupled with blockade of TNFα signaling, expanded VAT-Treg cells, resulting in protection from inflammation and improved metabolic indices, including promotion of insulin sensitivity. These studies suggest that antigen-specific targeting of VAT-localized Treg cells could eventually be a strategy for improving metabolic disease.
Highlights
Foxp3+CD4+ T regulatory (Treg) cells restrain most types of immune response, guarding against run-away reactions (Sakaguchi et al, 2008)
We generated a yeast library expressing a small number of randomly inserted mutations in the mini peptide-Ab construct using an error-prone polymerase chain reaction strategy (PCR; up to 3 to 5 mutations per kbp), which we selected with the YAe-62.8 TCR (YAe) T-cell receptor (TCR)
We investigated whether Fat1562 immunization of wild-type B6 mice would elicit expansion of particular Treg clones in visceral adipose tissue (VAT), and whether their TCRs would resemble the vTreg53 TCR. 16–20 week-old B6 mice were immunized with Fat1562 using the prime and boost scheme (Figure 4—figure supplement 1A), and the Fat1562-reactive CD4+ T cells were characterized by staining with the Fat1562/Ab-PE tetramer
Summary
Foxp3+CD4+ T regulatory (Treg) cells restrain most types of immune response, guarding against run-away reactions (Sakaguchi et al, 2008). Almost all Treg-cell studies focused on those circulating through or residing in lymphoid organs, so that our view of Treg-cell phenotype and function was heavily colored by the biology of this constellation of cells. Some of our attention has turned to distinct populations of Treg cells that operate in non-lymphoid organs, where they rein in local immune responses, and help maintain tissue homeostasis (Panduro et al, 2016). ‘Tissue-Tregs,’ as they have been termed, have distinct transcriptomes, T-cell receptor (TCR) repertoires, and dependencies that optimally arm them to survive and function within a particular tissue. A paradigmatic tissue-Treg population is that found in visceral adipose tissue (VAT), in particular in the male gonadal fat depot (Mathis, 2013).
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