Primary infection with the human herpesvirus, Epstein-Barr virus (EBV), may result in subclinical seroconversion or may appear as infectious mononucleosis (IM), a lymphoproliferative disease of variable severity. Why primary infection manifests differently between patients is unknown, and, given the difficulties in identifying donors undergoing silent seroconversion, little information has been reported. However, a longstanding assumption has been held that IM represents an exaggerated form of the virologic and immunologic events of asymptomatic infection. T-cell receptor (TCR) repertoires of a unique cohort of subclinically infected patients undergoing silent infection were studied, and the results highlight a fundamental difference between the 2 forms of infection. In contrast to the massive T-cell expansions mobilized during the acute symptomatic phase of IM, asymptomatic donors largely maintain homeostatic Tcell control and peripheral blood repertoire diversity. This disparity cannot simply be linked to severity or spread of the infection because high levels of EBV DNA were found in the blood from both types of acute infection. The results suggest that large expansions of T cells within the blood during IM may not always be associated with the control of primary EBV infection and that they may represent an overreaction that exacerbates disease. IntroductionEpstein-Barr virus (EBV) is a ␥ herpesvirus that persists for life in humans as a latent infection of B cells under the immunosurveillance of CD8 ϩ ␣␤ cytotoxic T lymphocytes (CTLs) (reviewed in Khanna and Burrows 1 ). An interesting enigma in EBV biology is the variable nature of primary infection. At one extreme, seroconversion can occur asymptomatically, whereas at the other extreme, mild to severe clinical manifestations of the lymphoproliferative disease infectious mononucleosis (IM) develop. Little is known about the immunologic and virologic parameters of silent infection except that it occurs most commonly in early childhood 2,3 without significant blood lymphocytosis and with reduced and delayed titers of viral antibodies. 2 In contrast, the overt clinical signs of IM (fever, lymphadenopathy, tonsillitis, and splenomegaly) have provided an experimental window for studying this form of primary infection. This self-limiting disease is typified by an increased systemic viral load [4][5][6] and, in common with many other acute viral infections (eg, human immunodeficiency virus [HIV], lymphocytic choriomeningitis virus [LCMV], simian immunodeficiency virus), 7-10 by a vigorous immune response of proliferating CD8 ϩ ␣␤-expressing T cells. 11 Tracking studies using EBV-specific major histocompatibility complex class 1 tetramers have confirmed that most of these T-cell expansions are virus specific. 12 It is unclear, however, whether these T cells play a pathologic or a protective role in IM. Resolution of the disease and transition to the long-term state of virus carrier are accompanied by a decrease in the numbers of virus-specific cytotoxic T lymphocy...

Increased pCTL reactivity to latent EBV CTL epitopes is coincident with recovery from disease after adoptive transfer of autologous CTL. Furthermore, the results are compatible with the belief that activation of a sustained CTL response to EBV latent epitopes is protective and may be a characteristic of patients in long-term remission from PTLD.

Immunosuppression resulting in impaired Epstein-Barr virus (EBV)-specific T-cell immunity is involved in the pathogenesis of EBV-positive post-transplantation lymphoproliferative disorder (EBV ؉ PTLD).Restoration of EBV-specific T-cell immunity by adoptive immunotherapy can induce remission. EBV-nuclear antigen-1 (EBNA1) is unique in being expressed in all cases of EBV ؉ PTLD. Recent data demonstrate that EBNA1 is not immunologically silent and can be exploited as a T-cell target. There are no data on EBNA1-specific T cells in PTLD. EBNA1-specific T cells capable of proliferation, interferon-␥ release, and CD107a/b degranulation were assayed in 14 EBV ؉ PTLD diagnostic blood samples and 19 healthy controls. EBNA1-specific CD4 ؉ T cells predominated and were expanded in 10 of 14 patients and 19 of 19 controls. Although human leukocyte antigen class I alleles influenced the magnitude of the response, EBNA1-specific CD8 ؉ effector T cells were successfully generated in 9 of 14 EBV ؉ PTLD patients and 16 of 19 controls. The majority of PTLD patients had a polymorphism in an EBNA1 epitope, and T-cell recognition was greatly enhanced when EBNA1 peptides derived from the polymorphic epitope were used. These results indicate that EBNA1-specific T cells should be included in adoptive immunotherapy for PTLD. Furthermore, expansion protocols should use antigenic sequences from relevant EBV strains. (Blood. 2010;116(13):2245-2252) IntroductionPost-transplantation lymphoproliferative disorder (PTLD) encompasses the spectrum of lymphoproliferative diseases that arise as a complication of organ transplantation. The incidence of PTLD varies depending on the type of organ transplanted (up to 30% for lung and small bowel transplantations vs 1%-5% for renal, cardiac, and liver transplantations) and the degree of immunosuppression. 1 Management remains suboptimal, relapses are frequent, and treatment-related mortality is high. 2 The rise in solid-organ transplantation, including high-risk solid-organ transplantation requiring more intense immunosuppression, coupled with improvements in long-term survival will probably result in a rise in the incidence of PTLD.The majority of PTLD cases (50%-80%) are positive for Epstein-Barr virus (EBV ϩ PTLD). EBV is an oncogenic ␥-herpes virus that infects more than 90% of adults worldwide. After primary infection, the virus persists for life within B cells. This asymptomatic state is, in part, maintained by T-cell-mediated immune control. 3 EBV ϩ PTLD arises partly as an iatrogenic consequence of immunosuppression resulting in the loss of antiviral immunity. 4 However, reduction of immunosuppression fails to induce a response in the majority of cases, suggesting that other mechanisms, including intratumoral immunosuppression, could operate in established PTLD. The expression of EBVlatent antigens in EBV ϩ PTLD provides an ideal target for in vitro-generated tumor antigen-specific T cells in an environment free from the constraints of ongoing iatrogenic and/or lymphomamediated immunosuppression. ...