IL-15-Dependent Induction of 4-1BB Promotes Antigen-Independent CD8 Memory T Cell Survival

• Published in: Journal of Immunology 2006-03, Vol.176 (5), p.2739-2748
• Main Authors: Pulle, Gayle, Vidric, Mariana, Watts, Tania H
• Format: Article
• Language: English
• Subjects: 4-1BB Ligand; Animals; Antigens - physiology; Antigens, CD - biosynthesis; Antigens, CD - genetics; Bone Marrow Cells - immunology; CD8-Positive T-Lymphocytes - cytology; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell Survival - immunology; Cells, Cultured; Gene Expression Regulation - immunology; Immunologic Memory; Influenza virus; Interleukin-15 - physiology; Mice; Mice, Congenic; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Mitogen-Activated Protein Kinases - physiology; Receptors, Nerve Growth Factor - biosynthesis; Receptors, Nerve Growth Factor - genetics; Receptors, Tumor Necrosis Factor - biosynthesis; Receptors, Tumor Necrosis Factor - genetics; Tumor Necrosis Factor Receptor Superfamily, Member 9; Tumor Necrosis Factors - genetics; Tumor Necrosis Factors - metabolism
• ISSN: 0022-1767; 1550-6606; 1365-2567
• DOI: 10.4049/jimmunol.176.5.2739

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.