Figure 6.

(A–C) Thirteen LN Treg specific cytokines, 16 Int Treg-specific cytokines, and 44 VAT Treg-specific cytokines are identified, which mediate 20 immune signaling pathways after screening for total 1,176 cytokines and their interactors (https://www.proteinatlas.org/search/cytokine) (logFC) in four tissues we studied indicated important influence of Treg in cytokine production and modulation of tissue specific microenvironment. Enriched pathway analysis by metascape showed that JAT-STAT signaling pathway and cytokine-cytokine receptor interaction were both modulated by up- and downregulated cytokines in Treg. One interesting finding was that although we have identified that IL2 may be the upstream regulator of Treg modulation; and its receptor IL2RB could induce this modulation, IL2 was downregulated in Treg from Int and VAT, which means a possibility that other interactors of IL2RB participate in this process. As IL2RB could interacts with Jak1 and RACK-1 according to NIH-NCBI Gene database (https://www-ncbi-nlm-nih-gov.libproxy.temple.edu/gene/3560). The metascape analysis also showed the important role of Jak-STAT signaling pathway, which may be a significant pathway in the modulation process of Treg, especially in non-lymphoid tissues such as int and VAT. See the detailed data in Supplementary Figure 5 .