IL-15-dependent induction of 4-1BB promotes antigen-independent CD8 memory T cell survival.
Mice lacking CD137L (4-1BBL) show normal primary expansion and contraction of the CD8+ T cell response to influenza virus, but exhibit a defect in Ag-specific CD8+ T cell numbers at 3-6 wk postinfection. Previous results showed that the decrease in CD8+ T cell numbers in this model is not due to a programming defect during primary expansion. Thus, it appears that 4-1BB/4-1BBL interactions control the number of surviving CD8+ effector memory cells, late in the primary response. In this report, we asked how 4-1BB on T cells could play a role after Ag has apparently been cleared from the host. We show that IL-15, a cytokine involved in regulation of CD8+ memory T cell survival, induces the expression of 4-1BB on CD8+CD44(high) memory phenotype T cells, but not on CD4+ T cells. The Ag-independent induction of 4-1BB by IL-15 was dependent on MAPK p38 and ERK activation. Transfer of in vitro-generated OT-I CD8+ memory T cells into unimmunized wild-type or 4-1BBL-deficient hosts revealed a 2- to 3-fold survival advantage when 4-1BBL was present, recapitulating the effect seen in the endogenous response to influenza in mice. Decreases in the overall number of memory CD8+ T cells were also observed in the bone marrow of unmanipulated 4-1BBL-deficient mice. These data suggest a model whereby 4-1BB expression on memory CD8+ T cells, perhaps due to encounter with IL-15 in the bone marrow, allows 4-1BB/4-1BBL interactions to maintain memory CD8 T cell survival in the absence of Ag.
Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
Gayle
G
Pulle
Mariana
M
Vidric
Tania H
TH
Watts
D053330:4-1BB Ligand; D000818:Animals; D000941:Antigens / Q000502:physiology*; D015703:Antigens, CD / Q000096:biosynthesis* / Q000235:genetics; D001854:Bone Marrow Cells / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D002470:Cell Survival / Q000276:immunology; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000276:immunology; D007156:Immunologic Memory; D019409:Interleukin-15 / Q000502:physiology*; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D017475:Receptors, Nerve Growth Factor / Q000096:biosynthesis* / Q000235:genetics; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis* / Q000235:genetics; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D048069:Tumor Necrosis Factors / Q000235:genetics / Q000378:metabolism
D053330:4-1BB Ligand; D000941:Antigens; D015703:Antigens, CD; D019409:Interleukin-15; 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; D048069:Tumor Necrosis Factors; D020928:Mitogen-Activated Protein Kinases