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Unconventional T cells are gaining center stage as important effector and regulatory cells that orchestrate innate and adaptive immune responses. Human Vγ9/Vδ2 T cells are amongst the best understood unconventional T cells, as they are easily accessible in peripheral blood, can readily be expanded and manipulated in vitro, respond to microbial infections in vivo and can be exploited for novel tumor immunotherapies. We here review findings that suggest that Vγ9/Vδ2 T cells, and possibly other unconventional human T cells, play an important role in bridging innate and adaptive immunity by promoting the activation and differentiation of various types of antigen-presenting cells (APCs) and even turning into APCs themselves, and thereby pave the way for antigen-specific effector responses and long-term immunological memory. Although the direct physiological relevance for most of these mechanisms still needs to be demonstrated in vivo, these findings may have implications for novel therapies, diagnostic tests and vaccines., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Infection in humans has been linked with altered cytokine gene transcription. It is unclear whether this phenomenon is a consequence of an established disease process or precedes the infective process. The primary end point of this study was to determine whether hospital-acquired pneumonia (HAP) was associated with differential gene expression of interferon (IFN)-γ, tumor necrosis factor (TNF)-α, and IL-23p19. The secondary end point was to identify whether alteration in gene expression preceded the clinical onset of infection., Methods: Sixty consecutive patients undergoing elective thoracic surgery were recruited. HAP was diagnosed as per National Nosocomial Infection Surveillance guidelines. Messenger RNA (mRNA) and protein levels were analyzed preoperatively and 24 h and 5 days postoperatively., Results: Forty-one patients had an uncomplicated recovery. Nineteen patients developed HAP. IL-6, IL-10, IL-12p35, IL-23p19, IL-27p28, TNF-α, and IFN-γ mRNA and protein levels of IL-6, IL-23, and IFN-γ in peripheral blood leukocytes were analyzed before surgery and 24 h and 5 days postsurgery. IL-23p19 mRNA levels were reduced in the pneumonia group (median, 4.19; 10th-90th centile range, 3.90-4.71) compared with the nonpneumonia group (4.50; 3.85-5.32) day 1 postsurgery (P=02). IFN-γ mRNA levels were reduced in the pneumonia group (2.48; 1.20-3.20) compared with nonpneumonia group (2.81; 2.10-3.26) (P=03) day 5 postsurgery. Results are expressed as log to base 10 copy numbers of cytokine mRNA per 10 million β-actin mRNA copy numbers. All values are given as median and 10th to 90th centile range., Conclusions: Cytokine gene expression is altered immediately following surgery in patients with postoperative HAP.

Background/aims: Association of hepatitis C virus (HCV) with increased autoantibodies, mixed cryoglobulinaemia, non-Hodgkin's B-cell lymphoma and increased peripheral innate (CD5(pos)) B cells suggests a role for B-lymphocytes in the pathogenesis of HCV-infection., Methods: Flow cytometry was used to estimate CD5(pos) B cell levels and CD81 co-expression in chronic HCV infection. Viral load was assessed using PCR., Results: We demonstrate expansion of innate B cells in HCV-infected liver from patients with fibrosis score less than stage II (39%, % of total B cells, P=0.002) and end stage HCV cirrhosis (20%, P<0.05) compared with normal liver (8%). Expression of CD81, a signal transducing molecule and putative HCV receptor, was significantly increased on peripheral blood CD5(pos) B cells compared with conventional B cells (P=0.0001). Higher levels of CD81 on CD5(pos) B cells were more dramatic in the liver of HCV-infected individuals. However, no significant difference was observed in the viral load of CD5(pos)CD81(High) B cells and CD5(neg)CD81(Low) B cells., Conclusions: Increased expression of CD81 on innate B cells, a population that is expanded in the livers and peripheral blood of chronic HCV-infected patients, suggests a role in viral specific activation and clonal proliferation in chronic HCV infection.

Background: Acute allograft rejection continues to be a major cause of morbidity following organ transplantation. The aim of this study was to investigate the local expression of a range of immunomodulatory molecules which may be mediating rejection of, or tolerance to, liver allografts., Methods: RNA was extracted from 31 protocol liver biopsies taken 7-10 days post-transplantation, reverse transcribed and screened by a sensitive RT-PCR for a wide range of cytokines and other immunomodulatory molecules. The mRNA profile of each biopsy was subsequently related to the histological and clinical status of the graft. Samples of RNA isolated from activated leukocytes and T cell clones, and from normal liver, were used as controls to compare to the 'immunological snapshot' obtained from the biopsies., Results: Presence of tumour necrosis factor-alpha, fas ligand, granzyme B and perforin mRNA in most of the liver biopsies reflected the occurrence of cell-mediated immune reactions. However, the expression of only one cytokine, interleukin-15 (IL-15), was significantly more frequent in allografts that showed no histological or biochemical signs of rejection during the early post-transplant period. Using an in vitro model it was demonstrated that recombinant IL-15 expands tenfold the number of CD3(+)CD56(+) (natural T; NT) cells from peripheral blood mononuclear cells cultures. Conditioning with IL-15 also increased cytotoxic activity of lymphocytes against leukaemic target cells., Conclusions: Although considerable evidence for cell-mediated immunity was shown for all liver allografts, the only clinical association was for IL-15 mRNA expression and graft acceptance. An in vitro model suggested that IL-15 may be enhancing the numbers and the activity of local regulatory cells, in particular resident NT cells in the liver, which may have a role in killing activated lymphocytes such as graft-reactive host T cells.

Background/aims: The intrahepatic immune system is likely to play a key role in determining the outcome of hepatitis C virus (HCV) infection. The hepatic lymphocyte repertoire is characterised by high CD8/CD4 T cell ratios and large numbers of gamma delta T cells, natural killer (NK) cells, NK T cells and NK receptor-positive T cells. It is not known which of these populations contribute to immunity against HCV or immune pathology., Methods: To explore the relative contributions of lymphocyte subpopulations, we have compared the intrahepatic lymphocyte repertoires and cytokine expression in 13 patients with mild chronic hepatitis C infection, 14 with end-stage hepatitis C cirrhosis and five histologically normal livers by flow cytometry and immunohistochemistry., Results: CD4(+) T cells bearing alpha beta T cell receptors (TCR) were significantly expanded in livers with chronic HCV infection while CD56(+) alpha beta T cells and V alpha 24 TCR-positive T cells were significantly depleted. Expanded CD4(+)T cells were predominantly Th1 cells, producing interferon-gamma but not interleukin-4., Conclusions: Failure to resolve HCV infection may be due to deficient innate and/or memory immune responses, while Th1 cells may mediate immune pathology.