Restoration of CD28 expression in CD28-CD8+ memory effector T cells reconstitutes antigen-induced IL-2 production

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.