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¹ Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109
² Department of Medicine, University of Washington, Seattle, WA 98195
³ Division of Pediatrics, City of Hope National Medical Center, Duarte, CA 90195
⁴ Department of Immunology, University of Washington, Seattle, WA 98195

Address correspondence to Stanley R. Riddell, MD Program in Immunology, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N., D3-100, Seattle, WA 98109. Phone: (206) 667-5249; Fax: (206) 667-7983; email: sriddell{at}fhcrc.org

The control of many persistent viral infections by Ag-specific cytolytic CD8⁺ T cells requires a concurrent virus-specific CD4⁺ Th cell response. This reflects in part a requirement of activated effector CD8⁺ T cells for paracrine IL-2 production as a growth and survival factor. In human CMV and HIV infection, the majority of differentiated virus-specific CD8⁺ T cells notably lose the ability to produce IL-2 but also lose expression of CD28, a costimulatory molecule. Analysis of the fraction of memory CD8⁺ T cells that continue to express CD28 revealed these cells retain the ability to produce IL-2. Therefore, we examined if IL-2 production by CD28^- CD8⁺ T cells could be restored by introduction of a constitutively expressed CD28 gene. Expression of CD28 in CD28^- CD8⁺ CMV- and HIV-specific CD8⁺ T cells reconstituted the ability to produce IL-2, which could sustain an autocrine proliferative response after Ag recognition. These results suggest that the loss of CD28 expression during differentiation of memory/effector CD8⁺ T cells represents a decisive step in establishing regulation of responding CD8⁺ T cells, increasing the dependence on CD4⁺ Th for proliferation after target recognition, and has implications for the treatment of viral disease with adoptively transferred CD8⁺ T cells.

Key Words: CD8⁺ T cells • CD28 • interleukin-2 • costimulation • memory response

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