Chronic graft-vs-host disease (GVHD) is a major cause of morbidity and mortality of long-term survivors of allogeneic hematopoietic cell transplantation (HCT). Chronic GVHD can have features of an autoimmune collagen vascular disease with clinical manifestations similar to autoimmune scleroderma and systemic lupus erythematosus (SLE). However, the pathogenesis of chronic GVHD is poorly understood. It is unclear how autoreactive T and B cells are generated in chronic GVHD recipients. We IntroductionChronic graft-versus-host disease (GVHD) is a serious and common long-term complication of allogeneic hematopoietic cell transplantation (HCT) occurring in 20% to 70% of patients surviving more than 100 days after HCT. [1][2][3][4] Despite improvements in the practice of allogeneic HCT over the last 25 years, there has been little change in the incidence, morbidity, and mortality of this complication. 3 One of the difficulties in combating chronic GVHD is the poor understanding of its pathogenesis.Chronic GVHD differs from acute GVHD in many aspects. First, the onset of acute GVHD is usually at 1 to 2 months following transplantation but the onset of chronic GVHD is usually delayed until 4 to 6 months after transplantation. 3 Second, although the target organ tissues of chronic GVHD are significantly overlapped with that of acute GVHD (ie, skin, gut, liver, and lung), the histopathology is distinguishably different. 3 While acute GVHD shows donor lymphocyte infiltration and host tissue-cell apoptosis and necrosis in target organs, chronic GVHD is featured by a marked increase in collagen deposition and a lack of T-lymphocyte infiltration in the target organ tissues. 3,4 Third, up to 70% of chronic GVHD patients have elevated levels of serum autoantibodies (eg, antinuclear, anti-dsDNA, and anti-smooth-muscle antibodies), 1,5,6 and depletion of B cells ameliorates refractory chronic GVHD in some patients. 3,7,8 Therefore, chronic GVHD has features similar to autoimmune collagen vascular disease such as scleroderma and systemic lupus erythematosus (SLE). 1,9 However, it is unclear how the autoimmune responses develop in chronic GVHD.Several murine HCT models have been used to study the pathogenesis of chronic GVHD. The first type of model is transplantation of parental lymphocytes into nonirradiated major histocompatibility complex (MHC)-mismatched F1 recipients. 10,11 In those models, the F1 recipients developed high levels of serum anti-dsDNA and glomerulonephritis, and the production of autoantibodies is a result of a cognate interaction between donor CD4 ϩ T cells and host B cells. [10][11][12][13][14][15] However, it is not clear whether the mechanisms revealed in those models reflect the pathogenesis of chronic GVHD in the irradiated HC transplant recipients.The second type of model is transplantation of donor lymphocytes into MHC-matched but minor antigen-mismatched irradiated recipients. In one model, donor LP/J (H-2 b ) bone marrow and spleen cells were transplanted into lethally irradiated C57BL/6 (H-2 b ) re...

Our findings suggest a potentially novel therapeutic approach to seasonal, zoonotic avian, and pandemic influenza-the use of phosphoantigens to activate gammadelta T cells against influenza virus infections.

As shown in humanized mice, a population of Vγ9Vδ2 T cells can reduce the severity and mortality of disease caused by infection with human and avian influenza viruses.

While few children and young adults have cross-protective antibodies to the pandemic H1N1 2009 (pdmH1N1) virus, the illness remains mild. The biological reasons for these epidemiological observations are unclear. In this study, we demonstrate that the bulk memory cytotoxic T lymphocytes (CTLs) established by seasonal influenza viruses from healthy individuals who have not been exposed to pdmH1N1 can directly lyse pdmH1N1-infected target cells and produce gamma interferon (IFN-␥) and tumor necrosis factor alpha (TNF-␣). Using influenza A virus matrix protein 1 (M1 58-66 ) epitope-specific CTLs isolated from healthy HLA-A2 ؉ individuals, we further found that M1 58-66 epitope-specific CTLs efficiently killed both M1 58-66 peptide-pulsed and pdmH1N1-infected target cells ex vivo. These M1 58-66 -specific CTLs showed an effector memory phenotype and expressed CXCR3 and CCR5 chemokine receptors. Of 94 influenza A virus CD8 T-cell epitopes obtained from the Immune Epitope Database (IEDB), 17 epitopes are conserved in pdmH1N1, and more than half of these conserved epitopes are derived from M1 protein. In addition, 65% (11/17) of these epitopes were 100% conserved in seasonal influenza vaccine H1N1 strains during the last 20 years. Importantly, seasonal influenza vaccination could expand the functional M1 58-66 epitope-specific CTLs in 20% (4/20) of HLA-A2 ؉ individuals. Our results indicated that memory CTLs established by seasonal influenza A viruses or vaccines had cross-reactivity against pdmH1N1. These might explain, at least in part, the unexpected mild pdmH1N1 illness in the community and also might provide some valuable insights for the future design of broadly protective vaccines to prevent influenza, especially pandemic influenza.

IntroductionCD4 ϩ CD25 ϩ Foxp3 ϩ regulatory T cells (Treg) are negative regulators of immune responses to self-and foreign antigens and play a critical role in maintaining immune tolerance by suppressing pathologic immune responses in autoimmune diseases, transplant allograft rejection, and graft-versus-host disease (GVHD). [1][2][3] On adoptive transfer in rodents, Treg were found to control experimental autoimmune diseases, 4 inhibit GVHD, 5,6 and prevent transplant allograft rejection, 7,8 indicating that Treg-based therapy has a great therapeutic potential for these diseases in humans.An important obstacle to Treg-based therapy has been the limited numbers of these cells that are available, as only approximately 1% to 2% of circulating human CD4 ϩ T cells are Treg. Several groups have developed protocols to expand a large number of polyclonal CD4 ϩ CD25 ϩ Treg in vitro with repeated stimulation by either CD3 and CD28 mAbs or artificial antigenpresenting cells (APCs) for activation through CD3 and CD28, together with exogenous high-dose interleukin-2 (IL-2). [9][10][11] However, polyclonal Treg may cause global immune suppression. 4,7 In addition, because there are only few antigen-specific Treg in the population of the polyclonal Treg, very large numbers of nonspecifically expanded Treg are required to inhibit bone-marrow allograft rejection in animal models. 12 All of these characteristics of polyclonal Treg hamper their clinical applications.In contrast, adoptive transfer of antigen-specific Treg has been shown to prevent and treat T cell-mediated inflammatory diseases with high efficiency. In animal models, small numbers of antigen-specific Treg can suppress experimental autoimmune diseases 13 and prevent GVHD and allograft rejection in bone marrow and solid organ transplantation. 14,15 Importantly, the transfer of antigen-specific Treg prevented target antigenmediated T-cell responses, such as GVHD and allograft rejection, but did not compromise host general immunity, including the graft-versus-tumor activity and antiviral immunity. 5,[15][16][17] Based on these studies, antigen-specific Treg has substantial promise for human immunotherapy.The reliable induction and expansion of rare antigen-specific Treg are technically challenging. Currently, several protocols for murine antigen-specific Treg induction and expansion have been reported in which either purified CD4 ϩ CD25 Ϫ or CD4 ϩ CD25 ϩ cells were cocultured with autologous dendritic cells (DCs) pulsed with alloantigen in the presence of high-dose IL-2 or directly cocultured with allogeneic DCs. 14,18-20 Similar protocol has also been reported for generation of human antigen-specific Treg recently. 21 In this protocol, antigen-specific CD4 ϩ CD25 ϩ Treg can be generated using the coculture of CD4 ϩ CD25 Ϫ T cells with allogeneic monocyte-derived DCs. However, the large-scale in vitro expansion of alloantigen-specific Treg is difficult because of certain features of DCs. For example, DCs are relatively rare in peripheral blood and are usually derived f...

Influenza is an acute respiratory viral disease that is transmitted in the first few days of infection. Evasion of host innate immune defenses, including natural killer (NK) cells, is important for the virus's success as a pathogen of humans and other animals. NK cells encounter influenza viruses within the microenvironment of infected cells and are important for host innate immunity during influenza virus infection. It is therefore important to investigate the direct effects of influenza virus on NK cells. In this study, we demonstrated for the first time that influenza virus directly infects and replicates in primary human NK cells. Viral entry into NK cells was mediated by both clathrin-and caveolin-dependent endocytosis rather than through macropinocytosis and was dependent on the sialic acids on cell surfaces. In addition, influenza virus infection induced a marked apoptosis of NK cells. Our findings suggest that influenza virus can directly target and kill NK cells, a potential novel strategy of influenza virus to evade the NK cell innate immune defense that is likely to facilitate viral transmission and may also contribute to virus pathogenesis.

Epstein-Barr virus-induced lymphoproliferative disease (EBV-LPD) after transplantation remains a serious and life-threatening complication. Herein we showed that the aminobisphosphonate pamidronate-expanded human Vγ9Vδ2-T cells efficiently killed EBV-transformed autologous lymphoblastoid B cell lines (EBV-LCL) through γ/δ-TCR and NKG2D receptor triggering and Fas and TRAIL engagement. By inoculation of EBV-LCL in Rag2(-/-)γc(-/-) mice and humanized mice, we established lethal EBV-LPD with characteristics close to those of the human disease. Adoptive transfer of pamidronate-expanded Vγ9Vδ2-T cells alone effectively prevented EBV-LPD in Rag2(-/-)γc(-/-) mice and induced EBV-LPD regression in EBV(+) tumor-bearing Rag2(-/-)γc(-/-) mice. Pamidronate treatment inhibited EBV-LPD development in humanized mice through selective activation and expansion of Vγ9Vδ2-T cells. This study provides proof-of-principle for a therapeutic approach using pamidronate to control EBV-LPD through Vγ9Vδ2-T cell targeting.

cd-T cells represent a small population of immune cells, but play an indispensable role in host defenses against exogenous pathogens, immune surveillance of endogenous pathogenesis and even homeostasis of the immune system. Activation and expansion of cd-T cells are generally observed in diverse human infectious diseases and correlate with their progression and prognosis. cd-T cells have both 'innate' and 'adaptive' characteristics in the immune response, and their anti-infection activities are mediated by multiple pathways that are under elaborate regulation by other immune components. In this review, we summarize the current state of the literature and the recent advancements in cd-T cell-mediated immune responses against common human infectious pathogens. Although further investigation is needed to improve our understanding of the characteristics of different cd-T cell subpopulations under specific conditions, cd-T cell-based therapy has great potential for the treatment of infectious diseases.