Phenotypic and Functional Changes of Cytotoxic CD56^posNatural T Cells Determine Outcome of Acute Hepatitis C Virus Infection

Abstract

Innate CD56pos natural killer (NK) and natural T (NT) cells comprise important hepatic antiviral effector lymphocytes whose activity is fine-tuned through surface NK receptors (NKRs). Dysregulation of NKRs in patients with long-standing hepatitis C virus (HCV) infection has been shown, but little is known regarding NKRs in acute infection. Treatment-naïve patients with acute HCV (n ‫؍‬ 22), including 10 with spontaneous recovery, were prospectively studied. CD56 pos NT levels were reduced early in acute HCV infection and did not fluctuate over time. In resolving HCV infection, NT cells with a more activated phenotype (lower CD158A and higher natural cytotoxicity receptor expression) at baseline predated spontaneous recovery. Moreover, NKG2A expression on CD56؉ NT cells correlated directly with circulating HCV RNA levels. Deficient interleukin-13 (IL-13) production by NT cells and reduced IL-2-activated killing (LAK) at baseline were associated with the ultimate development of persistence. These results indicate a previously unappreciated role for NT cells in acute HCV infection and identify a potential target for pharmacologic manipulation.

A different representation of natural T cells and natural killer cells between tumor-infiltrating and periphery lymphocytes in human hepatocellular carcinoma

“…Although it is well established that reduced CD8 + CTLs and increased FOXP3 + cells in HCC are coupled with poor prognosis (18,19), it is now also being recognized that the innate arm of the immune system may also perform a potentially important role in immune responses in liver diseases (25,(28)(29)(30)(31)(32). Suppressive innate immunocytes including regulatory DCs, γδ T cells and NKT cells have gained attention in previous years (15,(20)(21)(22).…”

KLRG1 Negatively Regulates Natural Killer Cell Functions through the Akt Pathway in Individuals with Chronic Hepatitis C Virus Infection

“…The majority (90%) of peripheral blood and spleen NK cells are CD56 dim and are considered to be the mature effectors, with enhanced natural and major histocompatibility complex (MHC)-unrestricted lymphokine-activated killing (LAK) ability, whereas a minority of the NK cells are CD56 bright , which function as an important source of immune-regulatory cytokines (16)(17)(18). Shifts of these subsets have been reported in patients with acute to chronic HCV infection and following antiviral therapy (10)(11)(12)(13)(14)(15). The antiviral activity of NK cells is regulated through surface NK receptors, including the inhibitory killer immunoglobulin-like receptors (KIRs) and the leukocyte immunoglobulin-like receptors (LIRs) in humans and the Ly49 molecules in mice.…”

“…Not surprisingly, HCV has evolved multiple strategies to counter the host's NK cell response (6). Compromised NK cell functions have been reported in chronically HCV-infected individuals, whereas normalization of depressed NK activity after antiviral therapy is associated with a low frequency of relapse and improved sustained virologic responses (SVR) (10)(11)(12)(13)(14)(15). Notably, aberrant NK activities may also contribute toward liver injury (8).…”

CD3⁺/CD16⁺CD56⁺ cell numbers in peripheral blood are correlated with higher tumor burden in patients with diffuse large B-cell lymphoma

“…+ T cells are not classical invariant NKT cells, but are a broader group of T cells matching the original definition of NKT cells [4,5]. Since there is only limited data on the role of NKT--like cells in malignant lymphomas, the objective of this study was to evaluate the frequency of NKT-like cells in the peripheral blood of DLBCL patients in correlation with clinical and laboratory parameters.…”

“…But it remains to be explained whether low NKT cell counts in the peripheral blood of patients with DLBCL are the result of their suppression by the tumor cells, or their migration to affected lymph nodes or organs. [3][4][5]. In contrast to CD4 and CD8 T cells, NKT cells recognize lipid antigens in the context of the major histocompatibility complex (MHC) class I-like antigen presenting molecule CD1d [6,7].…”