Cytotoxic CD4⁺ T cells in viral hepatitis

Abstract

CD4+ T cells are thought to contribute to antiviral immune responses by secretion of cytokines thereby providing help to CD8+ T and B cells. However, perforin-positive cytotoxic CD4+ T cells have been described in human immunodeficiency virus-positive patients suggesting a role not only of CD8+ but also of CD4+ T cells for killing virus-infected cells. We investigated 76 patients with viral hepatitis [15 hepatitis B virus (HBV), 22 HBV/hepatitis D virus and 17 hepatitis C virus (HCV)] for cytotoxic CD4+ T cells. The frequency of perforin-positive CD4+ T cells in viral hepatitis was highly variable ranging from < 1% to more than 25%. Perforin-positive CD4+ T cells displayed the phenotype of terminally differentiated effector cells (CD28-, CD27-). The highest frequencies of CD4+ cytotoxic T lymphocytes (CTLs) were found in patients with delta hepatitis (P = 0.04 vs HBV and HCV patients), and the presence of CD4+ CTLs was associated with elevated aspartate aminotransferase levels (P = 0.01) and decreased platelet counts (P = 0.03). Perforin-positive CD4+ T cells decreased in two individuals during spontaneous clearance of acute hepatitis C. Significant associations were found between the frequency of perforin-expressing CD4+ cells and age (P = 0.04), perforin-positive CD8+ cells (P < 0.001) and perforin-positive CD4-/CD8- lymphoid cells (P = 0.002). Differentiated CD27- effector CD4+ CTLs can be detected in patients with viral hepatitis. In particular in patients with more advanced liver disease, the accumulation of perforin-positive T cells with age could be one correlate for the more severe course of viral hepatitis in elderly individuals.

Existence of a weak cytotoxic CD4+ T cell population in mice infected with ectromelia virus

“…Clearly, CD4 + T cells re-stimulated with Pep3 were activated to elicit cytotoxicity against A20 cells. However, the killing level was rather low compared to that of CD8 + T cells against EMT6 cells, but consistent with that achieved with CD4 + T cells not re-stimulated but originating from infected mice and with that in (12) and similar to that achieved in (1). The results reported here show that although cytotoxicity is always associated with CD8 + T cells, there are viral infections in which this particular role is also shared with CD4 + T cells.…”

“…Also polyfunctional CD4 + T cells have been reported in viral infections. In terminal liver disease resulting from viral hepatitis, a population of highly cytotoxic CD4 + T cells have been reported (1). A recent report ascribes to the existence of a CD4 + T cell cytotoxic response in the acute phase of vaccinia virus infection (6).…”

Human CD4+T Cell Response to Human Herpesvirus 6

“…3F). CD4 ϩ T cells can function as effector cells capable of killing infected cells, in addition to their usual function in cytokine secretion (4,6,13,49,50,66). We investigated the cytolytic potential of the HHV-6-specific TCLs by measuring the expression of CD107a and CD107b, components of the lytic granule membrane that become surface accessible after degranulation (10,43), in combination with surface staining for CD4 and a conventional IFN-␥ intracellular staining assay.…”

Perforin level in CD4+ T cells from patients with systemic lupus erythematosus

“…The PRF1 gene is expressed primarily in NK cells and effector CD8 + T cells [31,32]. PRF1 is also expressed in a subpopulation of cytotoxic CD4 + T cells, which may combat various pathogens (33)(34)(35)(36)(37)(38)(39). An increased number of cytotoxic CD4 + T cells has been observed in patients with multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, and acute coronary syndromes [20][21][22][23].…”