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CD4⁺ T Cell-Induced Differentiation of EBV-Transformed Lymphoblastoid Cells Is Associated with Diminished Recognition by EBV-Specific CD8⁺ Cytotoxic T Cells ¹

Aaruni Khanolkar^*, Zheng Fu^*, L. Joey Underwood^*, Kristy L. Bondurant^*, Rosemary Rochford and Martin J. Cannon^2,*

^* Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, AR 72205; and Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI 48109

EBV transformation of human B cells in vitro results in establishment of immortalized cell lines (lymphoblastoid cell lines (LCL)) that express viral transformation-associated latent genes and exhibit a fixed, lymphoblastoid phenotype. In this report, we show that CD4⁺ T cells can modify the differentiation state of EBV-transformed LCL. Coculture of LCL with EBV-specific CD4⁺ T cells resulted in an altered phenotype, characterized by elevated CD38 expression and decreased proliferation rate. Relative to control LCL, the cocultured LCL were markedly less susceptible to lysis by EBV-specific CD8⁺ CTL. In contrast, CD4⁺ T cell-induced differentiation of LCL did not diminish sensitivity of LCL to lysis by CD8⁺ CTL specific for an exogenously loaded peptide Ag or lysis by alloreactive CD8⁺ CTL, suggesting that differentiation is not associated with intrinsic resistance to CD8⁺ T cell cytotoxicity and that evasion of lysis is confined to EBV-specific CTL responses. CD4⁺ T cell-induced differentiation of LCL and concomitant resistance of LCL to lysis by EBV-specific CD8⁺ CTL were associated with reduced expression of viral latent genes. Finally, transwell cocultures, in which direct LCL-CD4⁺ T cell contact was prevented, indicated a major role for CD4⁺ T cell cytokines in the differentiation of LCL.

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