Interindividual variation in human T regulatory cells

Abstract

Significance Control of immunologic tolerance and homeostasis rely on regulatory T lymphocytes that express the transcription factor FOXP3. To characterize the interindividual variation of human Treg cells, we performed a genome-wide expression and genotypic analysis of 168 human donors, healthy or affected by type-1 or type-2 diabetes (T1D, T2D). We identify cis -acting genetic variants that condition Treg effector but not specification genes, and gene clusters that suggest Treg-specific regulatory pathways for some key signature genes ( CTLA4 , DUSP4 ). We also identify factors that may control FOXP3 mRNA or protein expression, the specification of the Treg signature, and Treg suppressive efficacy. Although no single transcript correlates with diabetes, overall expression of the Treg signature is perturbed in T1D, but not T2D, patients.

Unstable FoxP3 + T regulatory cells in NZW mice

“…Perhaps surprisingly, in light of this apparently tight control, there is a wide range of variation in Treg proportions, with several studies having observed up to fourfold variation in the blood of healthy humans (e.g., refs. [24][25][26]. The same variation is observed among inbred mouse strains (27,28).…”

Diverse Gene Expression in Human Regulatory T Cell Subsets Uncovers Connection between Regulatory T Cell Genes and Suppressive Function

“…Second, another set of Treg cell genes (circle 2) was associated with both the suppression of zone A (blue) genes and induction of D (orange) genes, suggesting that these Treg cell genes counteract against the induction and suppression of the Teff cell genes triggered through CD3 stimulation. Third, the largest group of Treg genes (circle 3) was exclusively associated to suppress the zone A genes, which included CD101 tested in this study, and some key Treg cell genes such as HLADR, TNFRSF9, and DUSP4 (14,20,34). This analysis suggests that Treg cells may use two major sets of genes to modulate Teff gene responses in vitro: one counteracting Teff cell activation (zone A and D) and the other inducing an autoinhibitory mechanism (zone C).…”

“…Also, the DEGs were not uniformly higher or lower compared with Tconv cells (Fig. 1A, right columns), indicating that most of these DEGs were not part of the Treg cell signature (19,20). Gene Ontology analysis showed that the four groups have different expression of genes involved in T cell stimulation, nucleic acid sensing, and metabolic processes (Fig.…”

Deep phenotyping of Tregs identifies an immune signature for idiopathic aplastic anemia and predicts response to treatment

“…Nevertheless, when principal component analysis was performed, Treg B and T con had the most differences, whereas the Treg A subpopulation showed a transcriptional profile in between Treg B and T con (supplemental Figure 7). Comparing GEPs of Treg subpopulations to T con using the human Treg's gene signature 27 showed both Treg A and B subpopulations were significantly enriched in genes upregulated in human Tregs, including IL-2RA, FOXP3, IKZF2, TIGIT, and CTLA4 (false discovery rate [FDR] , 0.0001) for both Treg subpopulations compared with T con . Treg B cells were enriched with Treg-related memory/activation genes compared with Treg A, including JAKMIP1, CCR8, TRIB1, and GZMK (FDR , 0.0001, Figure 4C-E).…”