A Multifaceted Imbalance of T Cells with Regulatory... : Hepatology (original) (raw)

Autoimmune, Cholestatic and Biliary Disease

A Multifaceted Imbalance of T Cells with Regulatory Function Characterizes Type 1 Autoimmune Hepatitis†,‡

Ferri, Silvia*,1,2,§; Longhi, Maria Serena2; De Molo, Chiara1; Lalanne, Claudine1; Muratori, Paolo1; Granito, Alessandro1; Hussain, Munther J.2; Ma, Yun2; Lenzi, Marco1; Mieli-Vergani, Giorgina2; Bianchi, Francesco B.1, ¶; Vergani, Diego2; Muratori, Luigi1, †

1 Department of Clinical Medicine, University of Bologna, Bologna, Italy

2 Institute of Liver Studies, King's College School of Medicine at King's College Hospital, Denmark Hill, London, United Kingdom

*Address reprint requests to: Silvia Ferri, Department of Clinical Medicine, University of Bologna, Via Massarenti, 40138 Bologna, Italy.

E-mail:[email protected]

Received September 02, 2009; accepted June 01, 2010; previously published online June 11, 2010

†These authors contributed equally to this work.

‡Potential conflict of interest: Nothing to report.

§Fax: +39 051 6363631

¶This article is dedicated to Francesco B. Bianchi, who died in March 2010.

Abstract

Immunotolerance is maintained by regulatory T cells (Tregs), including CD4+CD25hi, CD8+CD28−, γδ, and CD3+CD56+ [natural killer T (NKT)] cells. CD4+CD25hi cells are impaired in children with autoimmune hepatitis (AIH). Little is known about Tregs in adults with AIH. The aim of this study was to investigate the frequency and function of Treg subsets in adult patients with AIH during periods of active disease and remission. Forty-seven AIH patients (16 with active disease and 31 in remission) and 28 healthy controls were studied. Flow cytometry was used to evaluate surface markers and function-related intracellular molecules in γδ, CD8+CD28−, NKT, and CD4+CD25hi cells. CD4+CD25hi T cell function was determined by the ability to suppress proliferation and interferon gamma (IFN-γ) production by CD4+CD25− target cells. Liver forkhead box P3–positive (FOXP3+) cells were sought by immunohistochemistry. In AIH patients, particularly during active disease, CD4+CD25hi T cells were fewer, expressed lower levels of FOXP3, and were less effective at inhibiting target cell proliferation versus healthy controls. Moreover, although the numbers of CD8+CD28− T cells were similar in AIH patients and healthy controls, NKT cells were numerically reduced, especially during active disease, and produced lower quantities of the immunoregulatory cytokine interleukin-4 versus controls. In contrast, γδ T cells in AIH patients were more numerous versus healthy controls and had an inverted Vδ1/Vδ2 ratio and higher IFN-γ and granzyme B production; the latter was correlated to biochemical indices of liver damage. There were few FOXP3+ cells within the portal tract inflammatory infiltrate.

Conclusion:

Our data show that the defect in immunoregulation in adult AIH is complex, and γδ T cells are likely to be effectors of liver damage.