Regulatory T cell defects in adult autoimmune hepatitis
Authors: Silvia Ferri, Claudine Lalanne, Chiara Masi, Luigi Muratori
Journal: Journal of Hepatology (2012)

FOXP3+ regulatory T cells in autoimmune hepatitis are fully functional and not reduced in frequencyJournal of HepatologyVol. 57Issue 1PreviewThe pathogenesis of autoimmune hepatitis (AIH) is not understood, but it was suggested that AIH may be related to a numerical or functional impairment of CD4+CD25+FOXP3+ regulatory T cells (Treg), which are important mediators of immune tolerance to self-antigens. However, the role of Treg in AIH is not clear, since earlier studies reporting Treg impairment had used only CD25 as marker that cannot unambiguously distinguish Treg from activated effector T cells. Full-Text PDF Reply to: “Regulatory T cell defects in autoimmune hepatitis”Journal of HepatologyVol. 57Issue 5PreviewWe read with interest the comment by Ferri et al. to our paper on Tregs in autoimmune hepatitis (AIH) [1], in which they emphasise several discrepancies between their recently published findings [2] and ours. Ferri et al. explain these discrepancies by methodological differences; however, find it difficult to compare the methodologies. We are grateful for the opportunity to clarify our methodology in comparison to that used by Ferri et al. Full-Text PDF Open Access Peiseler et al. report that FOXP3pos regulatory T cells (Treg) in adult patients with autoimmune hepatitis (AIH) are “fully functional and not reduced in frequency” [[1]Peiseler M. Sebode M. Franke B. Wortmann F. Schwinge D. Quaas A. et al.FOXP3+ regulatory T cells in autoimmune hepatitis are fully functional and not reduced in frequency.J Hepatol. 2012; 57: 125-132Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar]. We wish to make a few comments. Quoting previous literature on Tregs in AIH [2Longhi M.S. Ma Y. Bogdanos D.P. Cheeseman P. Mieli-Vergani G. Vergani D. Impairment of CD4(+)CD25(+) regulatory T cells in autoimmune liver disease.J Hepatol. 2004; 41: 31-37Abstract Full Text Full Text PDF PubMed Scopus (336) Google Scholar, 3Longhi M.S. Hussain M.J. Mitry R.R. Arora S.K. Mieli-Vergani G. Vergani D. et al.Functional study of CD4+CD25+ regulatory T cells in health and autoimmune hepatitis.J Immunol. 2006; 176: 4484-4491Crossref PubMed Scopus (282) Google Scholar], the authors state that most information has been obtained in paediatric cases. We have published data on 47 adult patients with AIH type 1 confirming the findings obtained in the paediatric setting and reported that the frequency of CD4posCD25highFOXP3pos cells is markedly reduced in AIH compared to healthy subjects, that this decrease is more marked when the disease is more active and that the numerical impairment is mirrored by the defective ability of Treg cells to control proliferation of CD4posCD25neg target cells [[4]Ferri S. Longhi M.S. De Molo C. Lalanne C. Muratori P. Granito A. et al.A multifaceted imbalance of T cells with regulatory function characterizes type 1 autoimmune hepatitis.Hepatology. 2010; 52: 999-1007Crossref PubMed Scopus (151) Google Scholar]. We have also shown that the decrease in Tregs is paralleled by a numerical impairment in natural killer T (NKT) cells [[4]Ferri S. Longhi M.S. De Molo C. Lalanne C. Muratori P. Granito A. et al.A multifaceted imbalance of T cells with regulatory function characterizes type 1 autoimmune hepatitis.Hepatology. 2010; 52: 999-1007Crossref PubMed Scopus (151) Google Scholar], a subset of cells with regulatory properties, suggesting that, contrary to with what proposed by Peiseler et al., a broad immune-regulatory T cell defect is probably present in AIH. The contrasting peripheral blood results between Peiseler et al. and our study probably derive from methodological differences. It is, however, difficult to compare our methods with those used in their paper, as they do not describe in detail their methodology. The purity of their CD4posCD25high Treg is only 80–90%, and no data are provided to assess the efficiency of the purification protocol they have used (they refer to preliminary results, but do not show them) or whether their purified cells are CD127low. Moreover, in contrast to previous reports [2Longhi M.S. Ma Y. Bogdanos D.P. Cheeseman P. Mieli-Vergani G. Vergani D. Impairment of CD4(+)CD25(+) regulatory T cells in autoimmune liver disease.J Hepatol. 2004; 41: 31-37Abstract Full Text Full Text PDF PubMed Scopus (336) Google Scholar, 3Longhi M.S. Hussain M.J. Mitry R.R. Arora S.K. Mieli-Vergani G. Vergani D. et al.Functional study of CD4+CD25+ regulatory T cells in health and autoimmune hepatitis.J Immunol. 2006; 176: 4484-4491Crossref PubMed Scopus (282) Google Scholar], including ours [[4]Ferri S. Longhi M.S. De Molo C. Lalanne C. Muratori P. Granito A. et al.A multifaceted imbalance of T cells with regulatory function characterizes type 1 autoimmune hepatitis.Hepatology. 2010; 52: 999-1007Crossref PubMed Scopus (151) Google Scholar], Peiseler et al. use a Treg/T-effector ratio of 1/1 when assessing the suppressor function, while Tregs normally represent some 4% of the total CD4+ lymphocyte population in the human blood [[5]Buckner J.H. Mechanisms of impaired regulation by CD4(+)CD25(+)FOXP3(+) regulatory T cells in human autoimmune diseases.Nat Rev Immunol. 2010; 10: 849-859Crossref PubMed Scopus (612) Google Scholar]. Concerning the immunohistochemistry data, Peiseler et al. say that their results differ from ours [[4]Ferri S. Longhi M.S. De Molo C. Lalanne C. Muratori P. Granito A. et al.A multifaceted imbalance of T cells with regulatory function characterizes type 1 autoimmune hepatitis.Hepatology. 2010; 52: 999-1007Crossref PubMed Scopus (151) Google Scholar], as, in contrast to us, they find increased numbers of FOXP3pos cells within the inflammatory infiltrate of patients with AIH. In our study, FOXP3pos cells were detected in most liver biopsies from AIH patients, but they represented a small component of the portal tract inflammatory infiltrate. No comparison was made with normal or pathological control livers. As FOXP3pos cells are reportedly absent or scarce in the normal liver, when tested by immunohistochemistry [6Lan R.Y. Cheng C. Lian Z.X. Tsuneyama K. Yang G.X. Moritoki Y. et al.6. Liver-targeted and peripheral blood alterations of regulatory T cells in primary biliary cirrhosis.Hepatology. 2006; 43: 729-737Crossref PubMed Scopus (263) Google Scholar, 7Oo Y.H. Weston C.J. Lalor P.F. Curbishley S.M. Withers D.R. Reynolds G.M. et al.Distinct roles for CCR4 and CXCR3 in the recruitment and positioning of regulatory T Cells in the inflamed human liver.J Immunol. 2010; 184: 2886-2898Crossref PubMed Scopus (178) Google Scholar], it can be argued that we did find increased numbers of tissue FOXP3pos cells in AIH. In support of their findings, Peiseler et al. refer to Buckner’s review [[5]Buckner J.H. Mechanisms of impaired regulation by CD4(+)CD25(+)FOXP3(+) regulatory T cells in human autoimmune diseases.Nat Rev Immunol. 2010; 10: 849-859Crossref PubMed Scopus (612) Google Scholar], which quotes increased numbers of tissue FOXP3pos cells in human autoimmune disease, such as in the skin in psoriasis and in the gut in inflammatory bowel disease. Interestingly, in the same review [[5]Buckner J.H. Mechanisms of impaired regulation by CD4(+)CD25(+)FOXP3(+) regulatory T cells in human autoimmune diseases.Nat Rev Immunol. 2010; 10: 849-859Crossref PubMed Scopus (612) Google Scholar] Treg function is documented to be decreased in most human autoimmune diseases, including type 1 diabetes, multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis and psoriasis, in agreement with what reported by us [[4]Ferri S. Longhi M.S. De Molo C. Lalanne C. Muratori P. Granito A. et al.A multifaceted imbalance of T cells with regulatory function characterizes type 1 autoimmune hepatitis.Hepatology. 2010; 52: 999-1007Crossref PubMed Scopus (151) Google Scholar] and others [2Longhi M.S. Ma Y. Bogdanos D.P. Cheeseman P. Mieli-Vergani G. Vergani D. Impairment of CD4(+)CD25(+) regulatory T cells in autoimmune liver disease.J Hepatol. 2004; 41: 31-37Abstract Full Text Full Text PDF PubMed Scopus (336) Google Scholar, 3Longhi M.S. Hussain M.J. Mitry R.R. Arora S.K. Mieli-Vergani G. Vergani D. et al.Functional study of CD4+CD25+ regulatory T cells in health and autoimmune hepatitis.J Immunol. 2006; 176: 4484-4491Crossref PubMed Scopus (282) Google Scholar] in AIH. Of note, a numerical defect of peripheral Tregs has been reported in primary biliary cirrhosis (PBC), another autoimmune liver disease [[6]Lan R.Y. Cheng C. Lian Z.X. Tsuneyama K. Yang G.X. Moritoki Y. et al.6. Liver-targeted and peripheral blood alterations of regulatory T cells in primary biliary cirrhosis.Hepatology. 2006; 43: 729-737Crossref PubMed Scopus (263) Google Scholar]. In the same paper, the frequency of FOXP3pos cells within the CD3pos liver infiltrating T lymphocytes was approximately 12% in PBC, 18% in AIH, and 28% in chronic hepatitis C [[6]Lan R.Y. Cheng C. Lian Z.X. Tsuneyama K. Yang G.X. Moritoki Y. et al.6. Liver-targeted and peripheral blood alterations of regulatory T cells in primary biliary cirrhosis.Hepatology. 2006; 43: 729-737Crossref PubMed Scopus (263) Google Scholar], though a more recent paper by Oo et al. has reported a frequency of about 12% in both AIH and PBC [[7]Oo Y.H. Weston C.J. Lalor P.F. Curbishley S.M. Withers D.R. Reynolds G.M. et al.Distinct roles for CCR4 and CXCR3 in the recruitment and positioning of regulatory T Cells in the inflamed human liver.J Immunol. 2010; 184: 2886-2898Crossref PubMed Scopus (178) Google Scholar]. As acknowledged by Peiseler et al. [[1]Peiseler M. Sebode M. Franke B. Wortmann F. Schwinge D. Quaas A. et al.FOXP3+ regulatory T cells in autoimmune hepatitis are fully functional and not reduced in frequency.J Hepatol. 2012; 57: 125-132Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar] and Bukner [[5]Buckner J.H. Mechanisms of impaired regulation by CD4(+)CD25(+)FOXP3(+) regulatory T cells in human autoimmune diseases.Nat Rev Immunol. 2010; 10: 849-859Crossref PubMed Scopus (612) Google Scholar], the use of FOXP3 as sole marker of Tregs in tissues is inadequate, FOXP3 being also expressed by effector T cells following activation [[5]Buckner J.H. Mechanisms of impaired regulation by CD4(+)CD25(+)FOXP3(+) regulatory T cells in human autoimmune diseases.Nat Rev Immunol. 2010; 10: 849-859Crossref PubMed Scopus (612) Google Scholar]: more accurate information will be obtained when better markers for immunohistochemical detection of Tregs become available. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.