CLINICAL IMMUNOLOGY AND IMMUNOPATHOLOGY Vol. 80, No. 3, September, pp. 266–272, 1996 Article No. 0122 Cytotoxic gd T Lymphocytes Associated with an Epstein–Barr Virus-Induced Posttransplantation Lymphoproliferative Disorder MARC E. ROTHENBERG,* , §WIM E. J. WEBER,† , §JANINA A. LONGTINE,‡ , § AND DAVID A. HAFLER† , § *Division of Immunology and Division of Hematology/Oncology, Department of Pediatrics, Children’s Hospital, Boston, Massachusetts 02115; †Center for Neurologic Diseases, Department of Neurology, and ‡Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts 02115; and §Harvard Medical School, Boston, Massachusetts 02115 T cells expressing the gd T cell receptor (TCR) have T cells expressing the gd T cell receptor have been been implicated in anti-EBV immunity (9 – 11). gd T implicated in anti-Epstein – Barr virus (EBV) immunity cells recognize heat shock proteins and recent data sug- and in the pathogenesis of autoimmune diseases of the gest that a subset (Vg2/Vd2) may selectively recognize central nervous system. However, they have never a nonprotein phosphonucleotide antigen found in a been isolated from human brain tissue for direct anal- number of microorganisms. We have observed a high ysis. We now report a 6-year-old girl with EBV-associ- frequency of gd T cells in brain lesions of patients with ated posttransplantation lymphoproliferative disease multiple sclerosis (12) and in the CSF of patients with involving inflammatory brain lesions. A high propor- subacute sclerosing panencephalitis (13); however, via- tion of gd T cells was found in the blood and in a brain ble gd T cells have not been directly isolated from brain lesion. Cultured T cell lines were found to have a re- tissue. markably high frequency of responsiveness to an EBV- We now report the case of a 6-year-old girl suffering transformed line, with a 17-fold enrichment in the from systemic PTLD with the unusual feature of brain lesion. These T cells expressed predominantly multifocal central nervous system (CNS) gray matter the gd T cell receptor and mediated non-MHC-re- lesions. gd T cells responsive to an EBV-infected B cell stricted cytotoxicity against EBV-infected target cells. line were identified at high frequency in her blood and These results provide the first demonstration of an as- in a brain lesion and were found to mediate HLA nonre- sociation of gd T cells with a posttransplantation lymphoproliferative disease and suggest a role of gd T stricted cytotoxicity of Epstein – Barr virus-infected cells in mediating inflammatory processes in the brain. target cells.  1996 Academic Press, Inc. CASE REPORT INTRODUCTION The patient was a female full-term product of healthy unrelated parents who was noted to have progressive irritability, failure to thrive, and organomegaly during Epstein – Barr virus (EBV) infections may give rise to different clinical syndromes depending upon the im- the first year of life. After the diagnosis of tyrosinemia, an orthotopic liver transplantation from an unrelated mune status of the host (1). In immunocompetent hosts, EBV infection results in infectious mononucleo- donor was performed at 18 months of life. The initial transplantation course was complicated by two mild sis and the EBV-infected B lymphocytes are effectively cleared by specific cytotoxic T lymphocytes. In contrast, episodes of acute rejection treated with OKT3, predni- sone, and cyclosporin A. Over the next 3 years, the in immunocompromised hosts with impaired T cell function, EBV infection may develop into a lymphoprol- patient had recurrent mild viral illnesses associated with cervical adenopathy and gingivoglossitis treated iferative disorder in approximately 1 – 10% of patients (2 – 8). For example, EBV can induce a posttransplanta- with acyclovir, one episode of cytomegalovirus colitis, and uncomplicated chicken pox. She did well develop- tion lymphoproliferative disorder (PTLD) following EBV infection secondary to the outgrowth of infected mentally and excelled to the top of her school class. She was eventually weaned to every other day predni- B lymphocytes. In the early stage, PTLD begins with a polyclonal expansion of EBV-infected B cells that can sone (5 mg) and maintained on cyclosporin A (150 mg bid). often resolve following reduction in the degree of immu- nosuppression. However, in the advanced stage, a At the age of 6 years, she began to develop recurrent fevers every 2–3 weeks. After 6 months, these fevers monoclonal expansion of EBV-infected lymphocytes oc- curs, resulting in a high rate of mortality. were associated with severe generalized lymphadenop- 266 0090-1229/96 $18.00 Copyright  1996 by Academic Press, Inc. All rights of reproduction in any form reserved. AID Clin 4195 / a505$$$141 07-18-96 19:18:48 clina AP: Clin