Biphasic role of 4-1BB in the regulation of mouse cytomegalovirus-specific CD8(+) T cells.
The initial requirement for the emergence of CMV-specific CD8(+) T cells is poorly understood. Mice deficient in the cosignaling TNF superfamily member, 4-1BB, surprisingly developed exaggerated early CD8(+) T-cell responses to mouse CMV (MCMV). CD8(+) T cells directed against acute MCMV epitopes were enhanced, demonstrating that 4-1BB naturally antagonizes these primary populations. Paradoxically, 4-1BB-deficient mice displayed reduced accumulation of memory CD8(+) T cells that expand during chronic/latent infection. Importantly, the canonical TNF-related ligand, 4-1BBL, promoted the accumulation of these memory CD8(+) T cells, whereas suppression of acute CD8(+) T cells was independent of 4-1BBL. These data highlight the dual nature of the 4-1BB/4-1BBL system in mediating both stimulatory and inhibitory cosignaling activities during the generation of anti-MCMV immunity.
Humphreys
Ian R
IR
Division of Molecular Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA. humphreysir@Cardiff.ac.uk
Lee
Seung-Woo
SW
Jones
Morgan
M
Loewendorf
Andrea
A
Gostick
Emma
E
Price
David A
DA
Benedict
Chris A
CA
Ware
Carl F
CF
Croft
Michael
M
D053330:4-1BB Ligand / Q000276:immunology*; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D004279:DNA, Viral / Q000737:chemistry / Q000235:genetics; D006566:Herpesviridae Infections / Q000276:immunology* / Q000821:virology; D007156:Immunologic Memory / Q000276:immunology; D007371:Interferon-gamma / Q000097:blood; D008168:Lung / Q000276:immunology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018146:Muromegalovirus / Q000276:immunology*; D016133:Polymerase Chain Reaction; D013154:Spleen / Q000276:immunology / Q000821:virology; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000037:antagonists & inhibitors / Q000276:immunology*; D014759:Viral Envelope Proteins / Q000737:chemistry / Q000235:genetics
D053330:4-1BB Ligand; D004279:DNA, Viral; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D014759:Viral Envelope Proteins; C040495:glycoprotein B, Simplexvirus; D007371:Interferon-gamma