CD4 T-cell help programs a change in CD8 T-cell function enabling effective long-term control of murine gammaherpesvirus 68: role of PD-1-PD-L1 interactions.
We previously showed that agonistic antibodies to CD40 could substitute for CD4 T-cell help and prevent reactivation of murine gammaherpesvirus 68 (MHV-68) in the lungs of major histocompatibility complex (MHC) class II(-/-) (CII(-/-)) mice, which are CD4 T cell deficient. Although CD8 T cells were required for this effect, no change in their activity was detected in vitro. A key question was whether anti-CD40 treatment (or CD4 T-cell help) changed the function of CD8 T cells or another cell type in vivo. To address this question, in the present study, we showed that adoptive transfer of CD8 T cells from virus-infected wild-type mice or anti-CD40-treated CII(-/-) mice caused a significant reduction in lung viral titers, in contrast to those from control CII(-/-) mice. Anti-CD40 treatment also greatly prolonged survival of infected CII(-/-) mice. This confirms that costimulatory signals cause a change in CD8 T cells enabling them to maintain effective long-term control of MHV-68. We investigated the nature of this change and found that expression of the inhibitory receptor PD-1 was significantly increased on CD8 T cells in the lungs of MHV-68-infected CII(-/-), CD40(-/-), or CD80/86(-/-) mice, compared with that in wild-type or CD28/CTLA4(-/-) mice, correlating with the level of viral reactivation. Furthermore, blocking PD-1-PD-L1 interactions significantly reduced viral reactivation in CD4 T-cell-deficient mice. In contrast, the absence of another inhibitory receptor, NKG2A, had no effect. These data suggest that CD4 T-cell help programs a change in CD8 T-cell function mediated by altered PD-1 expression, which enables effective long-term control of MHV-68.
Torrey Pines Institute for Molecular Studies, 3550 General Atomics Court, San Diego, California 92121, USA.
Peter
P
Dias
Francesca
F
Giannoni
Lian Ni
LN
Lee
Dongun
D
Han
Sorah
S
Yoon
Hideo
H
Yagita
Miyuki
M
Azuma
Sally R
SR
Sarawar
D019264:Adoptive Transfer; D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism*; D018122:B7-1 Antigen / Q000378:metabolism*; D060890:B7-H1 Antigen; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D019013:CD40 Antigens / Q000037:antagonists & inhibitors; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D008168:Lung / Q000821:virology; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010455:Peptides / Q000378:metabolism*; D061026:Programmed Cell Death 1 Receptor; D011485:Protein Binding; D018144:Rhadinovirus / Q000276:immunology*; D016019:Survival Analysis
D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; D019013:CD40 Antigens; C498919:Cd274 protein, mouse; D000949:Histocompatibility Antigens Class II; D008562:Membrane Glycoproteins; C491383:Pdcd1 protein, mouse; D010455:Peptides; D061026:Programmed Cell Death 1 Receptor