Functional impairment of CD8(+) T cells by regulatory T cells during persistent retroviral infection.
The establishment of viral persistence generally requires evasion of the host CD8(+) T cell response. Here we describe a form of evasion wherein the CD8(+) T cells are fully capable of recognizing their cognate antigen but their effector functions are suppressed by regulatory T cells. Virus-specific CD8(+) T cells adoptively transferred into mice persistently infected with Friend virus proliferated and appeared activated, but failed to produce IFNgamma or reduce virus loads. Cotransfer experiments revealed that a subpopulation of CD4(+) T cells from persistently infected mice suppressed IFNgamma production by the CD8(+) T cells. Treatment of persistently infected mice with anti-GITR antibody to ameliorate suppression by regulatory T cells significantly improved IFNgamma production by transferred CD8(+) T cells and allowed a significant reduction in viral loads. The results indicate that CD4(+) regulatory T cells contribute to viral persistence and demonstrate an immunotherapy for treating chronic retroviral infections.
Dittmer
Ulf
U
Institut für Virologie des Universitätsklinikums, 45122 Essen, Germany.
He
Hong
H
Messer
Ronald J
RJ
Schimmer
Simone
S
Olbrich
Anke R M
AR
Ohlen
Claes
C
Greenberg
Philip D
PD
Stromnes
Ingunn M
IM
Iwashiro
Michihiro
M
Sakaguchi
Shimon
S
Evans
Leonard H
LH
Peterson
Karin E
KE
Yang
Guojun
G
Hasenkrug
Kim J
KJ
D000208:Acute Disease; D019264:Adoptive Transfer; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D018984:Epitopes, T-Lymphocyte / Q000235:genetics; D005622:Friend murine leukemia virus / Q000276:immunology / Q000472:pathogenicity / Q000502:physiology; D015683:Gene Products, gag / Q000235:genetics / Q000276:immunology; D053450:Glucocorticoid-Induced TNFR-Related Protein; D007371:Interferon-gamma / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D017475:Receptors, Nerve Growth Factor / Q000037:antagonists & inhibitors / Q000276:immunology; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors / Q000276:immunology; D012192:Retroviridae Infections / Q000276:immunology* / Q000821:virology; D014412:Tumor Virus Infections / Q000276:immunology / Q000821:virology; D017735:Virus Latency
D000906:Antibodies; D018984:Epitopes, T-Lymphocyte; D015683:Gene Products, gag; D053450:Glucocorticoid-Induced TNFR-Related Protein; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C106544:Tnfrsf18 protein, mouse; D007371:Interferon-gamma