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


CONCLUSIONS
Our data demonstrate that Tregs can finely adapt, or even subvert, their classical inhibitory machinery in distinct microenvironments within the same organ.
Dipartimento di Medicina Interna e Specialità Mediche, "Sapienza" Università di Roma, Policlinico Umberto I, Rome, Italy.
Silvia
S
Piconese
Eleonora
E
Timperi
Ilenia
I
Pacella
Valeria
V
Schinzari
Claudio
C
Tripodo
Massimo
M
Rossi
Nicola
N
Guglielmo
Gianluca
G
Mennini
Gian Luca
GL
Grazi
Simona
S
Di Filippo
Stefania
S
Brozzetti
Katia
K
Fazzi
Guido
G
Antonelli
Maria Antonietta
MA
Lozzi
Massimo
M
Sanchez
Vincenzo
V
Barnaba
D000368:Aged; D000369:Aged, 80 and over; D006528:Carcinoma, Hepatocellular / Q000276:immunology* / Q000821:virology; D005260:Female; D006526:Hepatitis C / Q000150:complications / Q000276:immunology*; D006801:Humans; D051740:Ikaros Transcription Factor / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D008103:Liver Cirrhosis / Q000276:immunology* / Q000821:virology; D008113:Liver Neoplasms / Q000276:immunology* / Q000821:virology; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D053278:OX40 Ligand / Q000378:metabolism; D010641:Phenotype; D053262:Receptors, OX40 / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*; D015854:Up-Regulation
C111431:IKZF2 protein, human; D053278:OX40 Ligand; D053262:Receptors, OX40; C089251:TNFSF4 protein, human; D051740:Ikaros Transcription Factor; D018664:Interleukin-12