4-1BB and OX40 act independently to facilitate robust CD8 and CD4 recall responses.
Mice deficient in OX40 or 4-1BB costimulatory pathways show defects in T cell recall responses, with predominant effects on CD4 vs CD8 T cells, respectively. However, OX40L can also stimulate CD8 T cells and 4-1BBL can influence CD4 T cells, raising the possibility of redundancy between the two TNFR family costimulators. To test this possibility, we generated mice deficient in both 4-1BBL and OX40L. In an adoptive transfer model, CD4 T cells expressed 4-1BB and OX40 sequentially in response to immunization, with little or no overlap in the timing of their expression. Under the same conditions, CD8 T cells expressed 4-1BB, but no detectable OX40. Thus, in vivo expression of 4-1BB and OX40 can be temporally and spatially segregated. In the absence of OX40L, there were decreased CD4 T cells late in the primary response and no detectable secondary expansion of adoptively transferred CD4 T cells under conditions in which primary expansion was unaffected. The 4-1BBL had a minor effect on the primary response of CD4 T cells in this model, but showed larger effects on the secondary response, although 4-1BBL(-/-) mice show less impairment in CD4 secondary responses than OX40L(-/-) mice. The 4-1BBL(-/-) and double knockout mice were similarly impaired in the CD8 T cell response, whereas OX40L(-/-) and double knockout mice were similarly impaired in the CD4 T cell response to both protein Ag and influenza virus. Thus, 4-1BB and OX40 act independently and nonredundantly to facilitate robust CD4 and CD8 recall responses.
Dawicki
Wojciech
W
Department of Immunology, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada.
Bertram
Edward M
EM
Sharpe
Arlene H
AH
Watts
Tania H
TH
D053330:4-1BB Ligand; D019264:Adoptive Transfer / Q000379:methods; D000818:Animals; D015703:Antigens, CD; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000382:microbiology / Q000637:transplantation / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000382:microbiology / Q000637:transplantation / Q000821:virology; D049109:Cell Proliferation; D004768:Enterotoxins / Q000008:administration & dosage / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D007117:Immunization, Secondary / Q000379:methods; D007156:Immunologic Memory / Q000235:genetics; D009980:Influenza A virus / Q000276:immunology; D008024:Ligands; D008213:Lymphocyte Activation / Q000235:genetics; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D053278:OX40 Ligand; D017475:Receptors, Nerve Growth Factor / Q000096:biosynthesis / Q000502:physiology*; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis / Q000502:physiology*; D018089:Superantigens / Q000008:administration & dosage / Q000276:immunology; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D048069:Tumor Necrosis Factors
D053330:4-1BB Ligand; D015703:Antigens, CD; D004768:Enterotoxins; D018984:Epitopes, T-Lymphocyte; D008024:Ligands; D008562:Membrane Glycoproteins; D053278:OX40 Ligand; D017475:Receptors, Nerve Growth Factor; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor; D018089:Superantigens; C505717:Tnfrsf4 protein, mouse; C505715:Tnfrsf9 protein, mouse; C504586:Tnfsf4 protein, mouse; C505975:Tnfsf9 protein, mouse; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D014409:Tumor Necrosis Factor-alpha; D048069:Tumor Necrosis Factors; C026066:enterotoxin A, Staphylococcal