Functional CD8+ T cell responses in lethal Ebola virus infection.
Ebola virus (EBOV) causes highly lethal hemorrhagic fever that leads to death in up to 90% of infected humans. Like many other infections, EBOV induces massive lymphocyte apoptosis, which is thought to prevent the development of a functional adaptive immune response. In a lethal mouse model of EBOV infection, we show that there is an increase in expression of the activation/maturation marker CD44 in CD4(+) and CD8(+) T cells late in infection, preceding a dramatic rebound of lymphocyte numbers in the blood. Furthermore, we observed both lymphoblasts and apoptotic lymphocytes in spleen late in infection, suggesting that there is lymphocyte activation despite substantial bystander apoptosis. To test whether these activated lymphocytes were functional, we performed adoptive transfer studies. Whole splenocytes from moribund day 7 EBOV-infected animals protected naive animals from EBOV, but not Marburgvirus, challenge. In addition, we observed EBOV-specific CD8(+) T cell IFN-gamma responses in moribund day 7 EBOV-infected mice, and adoptive transfer of CD8(+) T cells alone from day 7 mice could confer protection to EBOV-challenged naive mice. Furthermore, CD8(+) cells from day 7, but not day 0, mice proliferated after transfer to infected recipients. Therefore, despite significant lymphocyte apoptosis, a functional and specific, albeit insufficient, adaptive immune response is made in lethal EBOV infection and is protective upon transfer to naive infected recipients. These findings should cause a change in the current view of the 'impaired' immune response to EBOV challenge and may help spark new therapeutic strategies to control lethal filovirus disease.
Bradfute
Steven B
SB
United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD 21702, USA.
Warfield
Kelly L
KL
Bavari
Sina
S
D019264:Adoptive Transfer; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D029043:Ebolavirus / Q000276:immunology* / Q000472:pathogenicity; D019142:Hemorrhagic Fever, Ebola / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D018960:Hyaluronan Receptors / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000276:immunology; D018655:Lymphocyte Count; D008379:Marburg Virus Disease / Q000276:immunology; D029024:Marburgvirus / Q000276:immunology / Q000472:pathogenicity; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D008969:Molecular Sequence Data; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000637:transplantation; D015854:Up-Regulation / Q000276:immunology
D018960:Hyaluronan Receptors