4-1BB Signaling Enhances Primary and Secondary Population Expansion of CD8+ T Cells by Maximizing Autocrine IL-2/IL-2 Receptor Signaling

4-1BB (CD137), a member of the tumor necrosis factor receptor superfamily (TNFRSF), is primarily expressed on activated T cells and is known to enhance proliferation of T cells, prevent activation-induced cell death, and promote memory formation of CD8(+) T cells. In particular, it is well acknowledged that 4-1BB triggering preferentially enhances the expansion of CD8(+) T cells rather than CD4(+) T cells, but the underlying mechanism remains unclear. Here we found that 4-1BB triggering markedly increased IL-2R alpha (CD25) and IL-2 expressions of CD8(+) T cells but minimally for CD4(+) T cells. Proliferation of CD8(+) T cells was moderately enhanced by direct 4-1BB triggering in the absence of signaling through IL2R alpha/IL-2 interactions, but further promoted in the presence of IL-2R alpha/IL-2 interactions. Among the TNFRSF members including OX40, GITR, CD30, and CD27, 4-1BB was superior in the ability to induce IL-2Ra expression on CD8(+) T cells. When the primary and secondary expansions of CD8(+) T cells in vivowere examined by adoptively transferring OVA-specific CD8(+) T cells along with the treatment with agonistic anti-4-1BB and/or antagonistic anti-CD25 F(ab') 2 mAb, 4-1BB triggering enhanced both primary and secondary expansion of CD8(+) T cells in vivo, and the 4-1BB effects were moderately suppressed in primary expansion while completely abolished in secondary expansion of OVA-specific CD8(+) T cells by blocking IL-2R alpha. These results suggest that 4-1BB-mediated increases of IL-2R alpha and IL-2 prolong the effects of transient TCR- and 4-1BB-mediated signaling in CD8(+) T cells, and that 4-1BB triggering preferentially enhances the expansion of CD8(+) T cells through the amplification of autocrine IL-2/IL-2R signaling loop.