CD161 expression on hepatitis C virus–specific CD8+ T cells suggests a distinct pathway of T cell differentiation

Abstract

Hepatitis C virus (HCV) causes chronic infection accompanied by a high risk of liver failure and hepatocellular carcinoma. CD8؉ T cell responses are important in the control of viremia. However, the T cell response in chronic infection is weak both in absolute numbers and in the range of epitopes targeted. In order to explore the biology of this response further, we analyzed expression of a panel of natural killer cell markers in HCV compared with other virus-specific T cell populations as defined by major histocompatibility complex class I tetramers. We found that CD161 was significantly expressed on HCV-specific cells (median 16.8%) but not on CD8؉ T cells specific for human immunodeficiency virus (3.3%), cytomegalovirus (3.4%), or influenza (3.4%). Expression was seen in acute, chronic, and resolved disease and was greatest on intrahepatic HCV-specific T cells (median 57.6%; P < 0.05). Expression of CD161 was also found on hepatitis B virus-specific CD8؉ T cells. In general, CD161؉CD8؉ T cells were found to be CCR7؊ "effector memory" T cells that could produce proinflammatory cytokines (interferon-␥ and tumor necrosis factor-␣) but contained scanty amounts of cytolytic molecules (granzyme B and perforin) and proliferated poorly in vitro. Expression of CD161 on CD8؉ T cells was tightly linked to that of CXCR6, a chemokine with a major role in liver homing. Conclusion: We propose that expression of CD161 indicates a unique pattern of T cell differentiation that might help elucidate the mechanisms of HCV immunity and pathogenesis. (HEPATOLOGY 2008;47:396-406.)

Human MAIT cells are xenobiotic-resistant, tissue-targeted, CD161hi IL-17–secreting T cells

“…On similar grounds, the significance of the high numbers of MAIT cells found in hepatitis C-infected livers becomes complex to assess because we show that they have a specific tropism for this organ. Indeed, the specific hepatitis C tetramer ϩ CD8 T cells studied previously 10 are CD161 int , suggesting that they are not MAIT cells.…”

“…The ability to secrete this cytokine has been previously correlated to the expression of RORC as well as CCR6 and CD161. 17 All these features are shared by the CD161 hi CD8 T-cell subset first implicated in viral hepatitis 10 before recently being further characterized by Billerbeck et al 11 These CD161 hi CD8 T cells share many characteristics with MAIT cells. They express an intermediate level of CD8␣␤ and many other markers that we found using phenotypic and transcriptional analysis, such as IL-23R and CCR2.…”

“…CD161 expression is found on a significant proportion of tissue-infiltrating T cells, such as the intestine and liver. [10][11][12] The frequency of these cells varies in certain pathologic conditions, such as cancer and viral or autoimmune diseases. [12][13][14][15] Recently, it has been demonstrated that a subset of naive cord blood CD4 T cells express CD161 and are precursors of peripheral, mature, Th17 T cells.…”

The role of chemokines in acute and chronic hepatitis C infection

“…72,122 The interaction of CXCL16 with CXCR6 on infiltrating lymphocytes has been shown to promote b1-integrin-mediated adhesion which may function in the retention of an inflammatory load within the portal tracts. 117 Thus, the CXCR6-CXCL16 axis may be important for regulatory and effector lymphocyte recruitment, but could have potential implications for the retention of these cells resulting in prolonged and inappropriate inflammatory responses.…”

“…59 CCL20 functions as a chemoattractant for CCR6 1 lymphocytes and DCs. 121,122 Serum levels of CCL20 are significantly elevated in chronic hepatitis and continue to increase with advancing fibrosis and cirrhotic disease. 122 Expression of this chemokine is also markedly increased in hepatoma cells and its levels correlate directly with VEGF expression and tumour size.…”