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ObjectiveMucosal-associated invariant T (MAIT) cells comprise a subpopulation of T cells that can be activated by bacterial products and cytokines to produce IFN-γ. Since little is known on MAIT cells during HCV infection, we compared their phenotype and function in comparison to HIV and HCV/HIV co-infected patients, and determined the effect of IFN-α-based and direct-acting antiviral therapy on MAIT cells of HCV patients.MethodsBlood samples from patients with chronic HCV (CHCV), virologically suppressed HIV, acute HCV/HIV co-infection (AHCV/HIV) and healthy individuals were examined by flowcytometry for phenotype and function of MAIT and NK cells.Results and ConclusionsCompared to healthy individuals, the frequency of CD161+Vα7.2+ MAIT cells was significantly decreased in patients with CHCV, HIV and AHCV/HIV co-infection. CD38 expression on MAIT cells was increased in AHCV/HIV patients. MAIT cells were responsive to IFN-α in vitro as evidenced by enhanced frequencies of IFN-γ producing cells. IFN-α-based therapy for CHCV decreased the frequency of IFN-γ+ MAIT cells, which was still observed 24 weeks after successful therapy. Importantly, even after successful IFN-α-based as well as IFN-α-free therapy for CHCV, decreased frequencies of MAIT cells persisted. We show that the frequencies of MAIT cells are reduced in blood of patients with CHCV, HIV and in AHCV/HIV co-infection compared to healthy individuals. Successful therapy for CHCV did not normalize MAIT cell frequencies at 24 weeks follow up. The impact of HIV and HCV infection on the numbers and function of MAIT cells warrant further studies on the impact of viral infections and the antimicrobial function of MAIT cells.

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During the past decade, increased emphasis has been placed on finding alternatives to IFN-α-based therapies. One such alternative, IFN-λ, has shown therapeutic promise in a variety of diseases, but research of this family of cytokines has been primarily focused on their antiviral activities. The goal of the present study was to investigate the role of IFN-λ in the regulation and modulation of B cell function. We show that, similar to IFN-α, IFN-λ1 is able to augment TLR-mediated B cell activation, partially attributed to an upregulation of TLR7 expression, and that both naïve and memory B cells express the limiting type III IFN receptor component, IFN-λR1. Furthermore, this IFN-λ-enhanced B cell activation resulted in increased cytokine and Ig production during TLR7 challenge, most prominently after the addition of helper T cell signals. Ultimately, these elevated cytokine and Ig levels could be partially attributed to the increase in proliferation of TLR7-challenged B cells by both type I and type III IFNs. These findings demonstrate the ability of IFN-λ to boost humoral immunity, an important attribute to consider for further studies on immunity to pathogens, vaccine development, and ongoing advancement of therapeutic strategies aimed at replacing IFN-α-based treatments with IFN-λ.

IntroductionIntravenous immunoglobulins (IVIgs) are pharmaceutical preparations of human IgG purified from pools of plasma of thousands of donors. For decades IVIgs have been established as treatment of autoantibody-mediated 1 and T-cell-mediated inflammatory disorders. 2 The distribution of IgG subclasses in IVIgs is comparable with that of IgG in normal human serum, however, unlike IgG purified from a single individual, therapeutic IVIg preparations contain substantial amounts of IgG dimers and traces of multimers, due to the idiotype-anti-idiotype complex formation between IgG molecules from different individuals. 3,4 In general, IVIgs were shown to be effective in conditions in which the immune system is hyperactive, but still the mechanisms of action by which IVIgs correct immune dysregulation are not fully understood. Various reports showed that the mode of actions of IVIgs is multifaceted and complex, involving interference with different components of the immune system. Clinical and immunologic improvements induced by IVIg treatment are reported to be profound and to extend the half-life of infused IgG, suggesting that IVIgs can modify cellular immune reactivity for prolonged periods. 1,5 Recently, we observed that hyperimmune IVIgs against hepatitis B surface antigen (HBs) protect against acute rejection after liver transplantation, indicating that IVIg treatment can modulate the T-cell-mediated immune response against alloantigens. 6 We and others found that in vitro both anti-HBs IVIgs and nonspecific IVIgs are able to suppress T-cell proliferation and cytokine production, and to impair the allogeneic T-cell stimulatory capacity of monocyte-derived and blood-derived dendritic cells (DCs), [6][7][8][9] demonstrating that IVIgs can suppress T-cell responses both during the priming phase as well as in the effector phase. The importance of DCs as a cellular target of IVIgs in vivo was recently shown in a murine model of immune thrombocytopenic purpura (ITP), in which treatment with IVIgs could be replaced by adoptive transfer of IVIg-treated DCs. 10 With regard to the mechanism by which IVIgs affect DC function, we found that the decreased T-cell stimulatory capacity of IVIg-treated DCs (IVIg-DCs) was associated with induction of cell death in mature DCs. Interestingly, IVIg treatment itself did not induce DC death directly, as the increased death of IVIg-DCs occurred only when cultured with other immune cells (ie, T cells and natural killer [NK] cells). 9 As activated NK cells are capable of killing DCs in a number of circumstances, 11,12 we hypothesized that NK cells may induce apoptosis of IVIg-DCs during the initial phase of DC-NK-cell encounter (ie, before the T-cell activation).Interactions between DCs and NK cells have been documented in a variety of settings, shedding light on the complexity of the bidirectional interaction between these 2 cell types. Bajenoff et al showed that NK cells are present in the medulla and the paracortex of lymph nodes, where they closely interact with DCs. Upon receivi...