Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 198, Issue 6, Pages 947-955Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20021288
Keywords
CD8+T cells; CD28; interleukin-2; costimulation; memory response
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Funding
- NCI NIH HHS [CA 18029, R01 CA033084, CA 33084, R37 CA033084, P01 CA018029] Funding Source: Medline
- NHLBI NIH HHS [HL 66947, U01 HL066947] Funding Source: Medline
- NIAID NIH HHS [AI 43650, AI 41754] Funding Source: Medline
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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.
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