## 7 HCV and Immune System
KIRs are essential in regulating NK cell activity, as their interaction with major histocompatibility complex (MHC) class I molecules determines whether NK cells execute cytotoxic responses or remain inhibited [52]. The engagement of NK cells in antiviral defense is particularly important in the initial phase of HCV infection, during which they contribute to an early reduction in systemic viral load through multiple mechanisms, including direct cytolysis of infected cells, secretion of antiviral cytokines, and the activation of other immune effectors. Following this initial innate immune response, the adaptive arm of the immune system is activated. Antigen-presenting cells (APCs), particularly dendritic cells (DCs), play a central role in bridging innate and adaptive immunity by processing and presenting viral antigens to naive T cells. DCs activate virus-specific CD4+ helper T cells, CD8+ cytotoxic T cells, and B cells, facilitating a coordinated immune response against HCV [53; 54; 55]. The interaction between dendritic cells and NK cells is mediated through the NKp30 receptor, which triggers the release of interleukin-12 (IL-12) and interleukin-15 (IL-15). These cytokines serve as potent activators of NK cell function, further enhancing their ability to produce IFN-\(\gamma\) and TNF-\(\alpha\). In turn, these cytokines contribute to the maturation and antigen-presenting capabilities of dendritic cells, reinforcing a positive feedback loop that amplifies antiviral immunity [56]. Beyond conventional NK cells, natural killer T (NKT) cells represent another subset of innate lymphoid cells involved in the immune response to HCV infection. These cells comprise approximately 26% of intrahepatic lymphocytes [57; 58] and are capable of secreting a range of cytokines, including IFN-\(\gamma\), TNF-\(\alpha\), and interleukin-2 (IL-2) [58]. The precise role of NKT cells in chronic HCV infection remains incompletely understood. However, existing evidence suggests that they may be involved in modulating the balance between T-helper 1 (Th1) and T-helper 2 (Th2) immune responses, which are crucial in determining the outcome of viral infections [59]. Studies examining the frequency of NKT cells in individuals with chronic HCV infection have reported conflicting findings. One study indicated an increased presence of NKT cells in the liver of chronically infected individuals [60], whereas another study suggested a significant reduction in their numbers [61]. Despite these discrepancies, functional analyses of NKT cells derived from HCV-infected patients have revealed alterations in their cytokine production profiles, specifically with regard to interleukin-13 (IL-13) secretion [62]. IL-13 is a cytokine predominantly associated with the Th2 immune response and exhibits considerable functional overlap with IL-4. It plays a critical role in regulating cell-mediated immunity and has also been implicated in the pathogenesis of allergic asthma [63]. Given its immunomodulatory properties, IL-13 may influence the progression of chronic HCV infection by shaping the inflammatory milieu within the liver. Taken together, these findings highlight the complexity of the innate immune response to HCV, particularly the roles of NK and NKT cells in viral control and immune modulation. While NK cells contribute to the early containment of HCV through cytolytic and cytokine-mediated mechanisms, NKT cells may be involved in orchestrating broader immunological shifts that impact disease progression. A summarization of the above-described HCV-immune system interplay can be found in Table 2.