SELECTIVE EXPANSION OF CYTOTOXIC T-LYMPHOCYTES WITH A CD4(-HELPER TYPE-1 PROFILE OF CYTOKINE SECRETION IN THE LIVER OF PATIENTS CHRONICALLYINFECTED WITH HEPATITIS-B VIRUS()CD56(+) SURFACE PHENOTYPE AND A T)

Highly purified CD4(+) T cells isolated from liver biopsies of patient s with hepatitis B virus-induced CAH had a strong cytotoxic activity a nd were comprised of a substantial number of cells (25%-40%) expressin g CD56 surface marker. These cells were absent in CD4(+). T cells from the peripheral blood of CAH patients or normal controls and these sus pensions did not have cytotoxic activity. CD4(+)CD56(+) T cells were f urther characterized by studies at the clonal level. A total of 71 hep atitis B envelope antigen-specific CD4(+) T cell clones was investigat ed (23 from liver biopsies, 48 from peripheral blood of patients or no rmal vaccinated individuals). A total of 16 out of 23 (69.5%) of the c lones from liver biopsies, but only 4.1% (2 out of 48) of those from P BLs, expressed CD56. A clone was defined as CD56(+) when 40% or more o f the cells expressed the marker. Production of TNF-alpha, IL-4, IL-5, IL-2, and IFN-gamma was investigated in 15 CD4(+)CD56(+) and in 18 CD 4(+)CD56(-) T cell clones, which shared the same HLA restriction eleme nt (DR2w15) and the same fine specificity (peptide 193-207 of the S re gion). All of the clones from the two groups released TNF-alpha and IL -2. However, all of the CD4(+)CD56(+) T cell clones produced IFN-gamma but not IL-4 and IL-5 (Th1-like cell clones). Fourteen of the CD4(+)C D56(-) clones released IFN-gamma, IL-4, and IL-5 (Th0-like cell clones ); three produced IL-4 and IL-5 but not IFN-gamma (Th2-like cell clone s); and only one had a Th1 cytokine secretion profile. Cell fractionat ing studies within single CD4(+)CD56(+) T cell clones showed that cell s expressing high density CD56 had a stronger cytotoxic activity and p roduced higher levels of IFN-gamma than cells with low density CD56, t hus further supporting a correlation between CD56 expression and cell functions. The results indicate that: 1) in CAH patients, cytotoxic CD 4(+) T cells with a Th1 cytokine secretion profile are compartmentaliz ed in the liver, 2) these cells may be identified by the expression of CD56, 3) the expansion of these cells may be facilitated by antigenic stimulation within the inflammatory environment of the liver, and 4) CD4(+)CD56(+) cells may play a pathogenetic role in hepatitis B virus infection.