IFN-induced attrition of CD8 T cells in the presence or absence of cognate antigen during the early stages of viral infections
Biochemistry & Molecular Pharmacology
Graduate School of Biomedical Sciences; Department of Pathology; Department of Molecular Genetics and Microbiology
Medical Subject Headings
Animals; Antigens, Viral; Apoptosis; CD8-Positive T-Lymphocytes; Computer Simulation; Glycoproteins; Immunity, Natural; Immunologic Memory; Interferons; Lymphocytic Choriomeningitis; Lymphocytic choriomeningitis virus; Mice; Mice, Knockout; Peptide Fragments; Poly I-C; Time Factors; Viral Proteins
Life Sciences | Medicine and Health Sciences
Profound lymphopenia has been observed during many acute viral infections, and our laboratory has previously documented a type I IFN-dependent loss of CD8 T cells immediately preceding the development of the antiviral T cell response. Most memory (CD44(high)) and some naive (CD44(low)) CD8 T cells are susceptible to IFN-induced attrition, and we show in this study that the IFN-induced attrition of CD8(+)CD44(high) T cells is associated with elevated activation of caspase-3 and caspase-8. We questioned whether TCR engagement by Ag would render CD8 T cells resistant to attrition. We tested whether a high concentration of Ag (GP33 peptide) would protect lymphocytic choriomeningitis (LCMV)-specific naive CD8 T cells (TCR transgenic P14 cells specific for the GP33 epitope of LCMV) and memory CD8 T cells (GP33-specific LCMV-immune cells) from depletion. Both naive P14 and memory GP33-specific donor CD8 T cells decreased substantially 16 h after inoculation with the Toll receptor agonist and IFN inducer, poly(I:C), regardless of whether a high concentration of GP33 peptide was administered to host mice beforehand. Moreover, donor naive P14 and LCMV-specific memory cells were depleted from day 2 LCMV-infected hosts by 16 h posttransfer. These results indicate that Ag engagement does not protect CD8 T cells from the IFN-induced T cell attrition associated with viral infections. In addition, computer models indicated that early depletion of memory T cells may allow for the generation for a more diverse T cell response to infection by reducing the immunodomination caused by cross-reactive T cells.
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Citation: J Immunol. 2006 Apr 1;176(7):4284-95.