A multifaceted imbalance of T cells with regulatory function characterizes type 1 autoimmune hepatitis.
Immunotolerance is maintained by regulatory T cells (Tregs), including CD4(+)CD25(hi), CD8(+)CD28(-), gammadelta, and CD3(+)CD56(+) [natural killer T (NKT)] cells. CD4(+)CD25(hi) 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 gammadelta, CD8(+)CD28(-), NKT, and CD4(+)CD25(hi) cells. CD4(+)CD25(hi) T cell function was determined by the ability to suppress proliferation and interferon gamma (IFN-gamma) 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(+)CD25(hi) 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, gammadelta T cells in AIH patients were more numerous versus healthy controls and had an inverted Vdelta1/Vdelta2 ratio and higher IFN-gamma 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.


CONCLUSIONS
Our data show that the defect in immunoregulation in adult AIH is complex, and gammadelta T cells are likely to be effectors of liver damage.
Ferri
Silvia
S
Department of Clinical Medicine, University of Bologna, Bologna, Italy. silvia.ferri9@unibo.it
Longhi
Maria Serena
MS
De Molo
Chiara
C
Lalanne
Claudine
C
Muratori
Paolo
P
Granito
Alessandro
A
Hussain
Munther J
MJ
Ma
Yun
Y
Lenzi
Marco
M
Mieli-Vergani
Giorgina
G
Bianchi
Francesco B
FB
Vergani
Diego
D
Muratori
Luigi
L
D000293:Adolescent; D000328:Adult; D000368:Aged; D018106:CD28 Antigens / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology / Q000502:physiology; D016022:Case-Control Studies; D049109:Cell Proliferation; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D053804:Granzymes / Q000378:metabolism; D019693:Hepatitis, Autoimmune / Q000145:classification* / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology / Q000473:pathology / Q000502:physiology; D008297:Male; D008875:Middle Aged; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000473:pathology* / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000473:pathology* / Q000502:physiology*; D055815:Young Adult
D018106:CD28 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D053645:Interleukin-2 Receptor alpha Subunit; D016692:Receptors, Antigen, T-Cell, gamma-delta; D007371:Interferon-gamma; D053804:Granzymes