A switch in costimulation from CD28 to 4-1BB during primary versus secondary CD8 T cell response to influenza in vivo.
4-1BBL(-/-) mice exhibit normal primary CD8 T cell responses to influenza virus, but show decreased CD8 T cell numbers late in the primary response as well as decreased secondary responses. In contrast, CD28(-/-) mice are defective in initial CD8 T cell expansion. Using agonistic anti-4-1BB Ab to replace the CD28 or 4-1BB signal, we examined the timing of the required signals for CD28 vs 4-1BB costimulation. A single dose of agonistic anti-4-1BB Ab added only during priming restores the secondary CD8 T cell response in CD28(-/-) mice. Once the T cell numbers in the primary response reach a minimum threshold, a full secondary response is achieved even in the absence of CD28. In contrast, anti-4-1BB added during priming fails to correct the defective secondary response in 4-1BBL(-/-) mice, whereas addition of anti-4-1BB during challenge fully restores this response. Thus, there is a switch in costimulatory requirement from CD28 to 4-1BB during primary vs recall responses. Adoptive transfer studies show that T cells primed in 4-1BBL(-/-) or wild-type mice are equally capable of re-expansion when rechallenged in wild-type mice. These studies rule out a model in which signals delivered through 4-1BB during priming program the T cells to give a full recall response and suggest that 4-1BB-4-1BBL interactions take place at later stages in the immune response. The results indicate that anti-4-1BB or 4-1BBL therapy will be most effective during the boost phase of a prime-boost vaccination strategy.
Bertram
Edward M
EM
Department of Immunology, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
Dawicki
Wojciech
W
Sedgmen
Bradley
B
Bramson
Jonathan L
JL
Lynch
David H
DH
Watts
Tania H
TH
D053330:4-1BB Ligand; D000818:Animals; D000914:Antibodies, Viral / Q000096:biosynthesis; D015703:Antigens, CD; D018106:CD28 Antigens / Q000235:genetics / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D007106:Immune Sera / Q000008:administration & dosage / Q000502:physiology; D007117:Immunization, Secondary / Q000379:methods; D007156:Immunologic Memory / Q000235:genetics; D009980:Influenza A virus / Q000276:immunology; D007252:Influenza Vaccines / Q000008:administration & dosage* / Q000276:immunology; D007274:Injections, Intraperitoneal; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009976:Orthomyxoviridae Infections / Q000235:genetics / Q000276:immunology; D017475:Receptors, Nerve Growth Factor / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency / Q000235:genetics
D053330:4-1BB Ligand; D000914:Antibodies, Viral; D015703:Antigens, CD; D018106:CD28 Antigens; D007106:Immune Sera; D007252:Influenza Vaccines; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C505715:Tnfrsf9 protein, mouse; C505975:Tnfsf9 protein, mouse; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D014409:Tumor Necrosis Factor-alpha