4-1BBL enhances anti-tumor responses in the presence or absence of CD28 but CD28 is required for protective immunity against parental tumors.
A20 is an aggressive BALB/c B cell lymphoma that, despite its expression of B7-2, rapidly forms tumors in syngeneic mice. We have generated A20 transfectants expressing elevated levels of B7-2 (A20/B7-2high) or 4-1BBL (A20/4-1BBL(low,mod,high)) and found that mice which were able to reject the A20/B7-2 or A20/4-1BBL transfectants were also resistant to subsequent systemic challenge with the parental cell line. To assess whether the effectiveness of 4-1BBL in enhancing anti-tumor immunogenicity was dependent on additional signals from B7-CD28 interaction, we injected the A20 variants into BALB/c CD28(-/-) mice. We found that CD28(-/-) mice were able to reject the A20/4-1BBL variants while A20/B7-2 cells formed tumors. However, when the A20/4-1BBL resistant CD28(-/-) mice were systemically challenged with the A20 parental line, tumors formed rapidly. Upon restimulation in vitro, splenocytes from A20/4-1BBL immunized CD28(+/+) mice were able to kill parental tumors whereas splenocytes from CD28(-/-) mice showed a reduction in CTL activity against A20 or A20/4-1BBL targets. Examination of cytokine production by the immunized animals indicated that the CD28(-/-) splenocytes secreted substantially less IL-2 as well as reduced levels of IFN-gamma compared with their CD28(+/+) counterparts. Thus, 4-1BBL expressing tumors are capable of priming CTL responses against 4-1BBL transfected as well as parental tumors in the absence of CD28. However, in the absence of CD28 signaling, the production of cytokines and particularly IL-2 was lower, resulting in a weaker CTL recall response and reduced ability to survive challenge with parental tumor.
Guinn
B A
BA
Department of Immunology, University of Toronto, Toronto, Ontario, M5S 1A8, Canada.
Bertram
E M
EM
DeBenedette
M A
MA
Berinstein
N L
NL
Watts
T H
TH
D053330:4-1BB Ligand; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics; D051940:B7-2 Antigen; D018106:CD28 Antigens / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D003601:Cytotoxicity Tests, Immunologic; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D008223:Lymphoma / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D013154:Spleen / Q000276:immunology; D016019:Survival Analysis; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014162:Transfection; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
D053330:4-1BB Ligand; D015703:Antigens, CD; D051940:B7-2 Antigen; D018106:CD28 Antigens; C497965:Cd86 protein, mouse; D007376:Interleukin-2; D008562:Membrane Glycoproteins; C505975:Tnfsf9 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma