IFN-induced attrition of CD8 T cells in the presence or absence of cognate antigen during the early stages of viral infections.
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.
Department of Pathology, Program in Immunology and Virology, University of Massachusetts Medical School, Worcester, 01655, USA.
Kapil
K
Bahl
Sung-Kwon
SK
Kim
Claudia
C
Calcagno
Dario
D
Ghersi
Roberto
R
Puzone
Franco
F
Celada
Liisa K
LK
Selin
Raymond M
RM
Welsh
D000818:Animals; D000956:Antigens, Viral / Q000276:immunology*; D017209:Apoptosis / Q000187:drug effects; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D003198:Computer Simulation; D006023:Glycoproteins / Q000276:immunology*; D007113:Immunity, Innate; D007156:Immunologic Memory; D007372:Interferons / Q000172:deficiency / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D008216:Lymphocytic Choriomeningitis / Q000276:immunology* / Q000473:pathology* / Q000821:virology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D010446:Peptide Fragments / Q000276:immunology*; D011070:Poly I-C / Q000494:pharmacology; D013997:Time Factors; D014764:Viral Proteins / Q000276:immunology*
D000956:Antigens, Viral; D006023:Glycoproteins; D010446:Peptide Fragments; D014764:Viral Proteins; C094244:glycoprotein peptide 33-41, Lymphocytic choriomeningitis virus; D007372:Interferons; D011070:Poly I-C