Human OX40 tunes the function of regulatory T cells in tumor and nontumor areas of hepatitis C virus-infected liver tissue

Abstract

Regulatory T cells (Tregs) can be considered as a mixed population of distinct subsets, endowed with a diverse extent and quality of adaptation to microenvironmental signals. Here, we uncovered an opposite distribution of Treg expansion, phenotype, and plasticity in different microenvironments in the same organ (liver) derived from patients with chronic hepatitis C: On the one side, cirrhotic and tumor fragments were moderately and highly infiltrated by Tregs, respectively, expressing OX40 and a T‐bethighIFN‐γ– “T‐helper (Th)1‐suppressing” phenotype; on the other side, noncirrhotic liver specimens contained low frequencies of Tregs that expressed low levels of OX40 and highly produced interferon‐gamma (IFN‐γ; T‐bet+IFN‐γ+), thus becoming “Th1‐like” cells. OX40‐expressing and Th1‐suppressing Tregs were enriched in the Helios‐positive subset, carrying highly demethylated Treg cell‐specific demethylated region that configures committed Tregs stably expressing forkhead box protein 3. OX40 ligand, mostly expressed by M2‐like monocytes and macrophages, boosted OX40+ Treg proliferation and antagonized the differentiation of Th1‐like Tregs. However, this signal is counteracted in noncirrhotic liver tissue (showing various levels of inflammation) by high availability of interleukin‐12 and IFN‐γ, ultimately leading to complete, full Th1‐like Treg differentiation. Conclusion: Our data demonstrate that Tregs can finely adapt, or even subvert, their classical inhibitory machinery in distinct microenvironments within the same organ. (Hepatology 2014;60:1494–1507)

Regulatory T cells with multiple suppressive and potentially pro-tumor activities accumulate in human colorectal cancer

“…First, we focused on the transcription factor Helios, which has been associated to the thymic origin, to a stronger suppressive function 15 and to a more stable regulatory program 16 maintained by epigenetic events, i.e., demethylation in the Treg-specific demethylated region (TSDR) of the FOXP3 locus. 1 The frequency of Helios high Tregs significantly increased only in T ( Fig. 2A-B), in line with data in hepatocellular carcinoma (HCC).…”

“…2A-B), in line with data in hepatocellular carcinoma (HCC). 1 Conversely, the proportion of Helios low Tregs accumulated in both NT and T, compared to PB, possibly as a physiological consequence of colonic Treg induction in response to food and microbial antigens. 17 To support the relationship between Helios expression and regulatory stability, we analyzed the level of TSDR methylation in highly purified Helios high or Helios low Tregs or Tconvs isolated from the PB or NT specimen (but not from T specimen, because of the paucity of lymphocytes extracted from the T district that did not allow these assays requiring very high number of cells).…”

“…1 Contrary to the majority of cancer types, in colorectal cancer (CRC), a high Treg density at the tumor site (evaluated by immunohistochemistry) has been associated to a better outcome. [2][3][4] This finding led to hypothesize that, in CRC, Treg-mediated suppression of chronic inflammation may prevail over the control of antitumor immunity.…”

“…1 Therefore, we performed multiparameter flow cytometry to better characterize Treg diversity in NT and T specimens from CRC patients. First, we focused on the transcription factor Helios, which has been associated to the thymic origin, to a stronger suppressive function 15 and to a more stable regulatory program 16 maintained by epigenetic events, i.e., demethylation in the Treg-specific demethylated region (TSDR) of the FOXP3 locus.…”

“…1 Based on the observation of a pivotal role of OX40 in supporting Treg fitness in experimental models of gut inflammation, 19,20 we investigated whether Treg expansion in CRC was related to higher levels of OX40 expression. Indeed, we found that the frequency of both OX40 C Tconvs and Tregs significantly increased in NT and much more in T samples (Fig.…”