Systemic Administration of IL-15 Augments the Antigen-Specific Primary CD8+ T Cell Response Following Vaccination with Peptide-Pulsed Dendritic Cells

Abstract

The systemic administration of IL-2 can act as a potent adjuvant for T cell-directed vaccine strategies. However, not only is the administration of IL-2 potentially toxic, but recent evidence suggests that it may also paradoxically limit the duration and magnitude of the cytotoxic T cell response. A recently identified cytokine, IL-15, shares many properties with IL-2 and may provide a preferential means of augmenting T cell-directed vaccine responses. Although well characterized in vitro, there are few data on the ability of IL-15 to augment T cell-mediated responses in vivo. We therefore evaluated the ability of systemic IL-15 to function as a T cell adjuvant in a murine vaccine model. To establish a population of easily identifiable Ag-responsive T cells, naive CD8+ (OT-1) T cells were first adoptively transferred into mice. Vaccination with peptide-pulsed dendritic cells induced a modest expansion of OT-1 T cells. The addition of systemic IL-15 for 7 days following vaccination resulted in a significant increase in the expansion of responding T cells in the PBL, spleen, and lymph nodes. Importantly, the responding T cells were cytotoxic and maintained a Tc1-biased phenotype. We did not observe either enhanced resistance to activation-induced cell death or preferential generation of memory T cells as a result of treatment with IL-15 compared with IL-2. These studies show for the first time that IL-15 is capable of augmenting the primary CD8+ T cell response to vaccination and contribute to the basis for future experiments exploring the clinical role of IL-15.

IL-7 and IL-15 differentially regulate CD8+ T-cell subsets during contraction of the immune response

“…Of note, the increased numbers and percentages of donor OT-I CD8 ϩ T cells observed after cytokine treatment were sustained in the PBLs and spleen ( Figure S2) at approximately 2 months after infection in agreement other studies. 11,14,16,17,40 However, the enhanced percentage of donor OT-I CD8 ϩ T cells induced after cytokine administration did appear to wane over extended periods of time ( Figure S2E), as has also been observed with other studies. 16,17,40 We also evaluated the response of endogenous CD8 ϩ T cells in mice infected with LM-OVA using H-2K b tetramers bound with the OVA-peptide (OVAp; Figure 1D).…”

“…Both IL-7 and IL-15 increased the number of antigen-specific CD8 ϩ T cells by approximately 10-fold in the spleen by the end of treatment ( Figure 1B) in agreement with previous studies. [11][12][13][14][15][16][17][18] Interestingly, in the spleen (data not shown) and peripheral blood lymphocytes (PBLs; Figure 1C), the percentage of donor T cells was much higher with IL-15 complexes than with IL-7 complexes. This difference highlights the ability of IL-7 complexes to increase total splenocyte cell numbers without as great a proportional impact on the percentage of antigen-specific CD8 ϩ T cells, possibly the result of the distinct ability of IL-7 complexes to expand immature B-cell precursors ( Figure S1C,D).…”

“…[4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] Early after infection, CD8 ϩ T-cell survival may be impaired in the absence of IL-7. 21 Furthermore, it was reported that effector CD8 ϩ T cells destined to become long-lived memory cells selectively express CD127, suggesting that these cells might be preferentially IL-7 dependent.…”

IL-15 Trans-Signaling with the Superagonist RLI Promotes Effector/Memory CD8+ T Cell Responses and Enhances Antitumor Activity of PD-1 Antagonists

“…Moreover, it has been suggested that IL-15 could favor maturation of dendritic cells, leading to augmentation of their Ag-presentation capacities (5). Finally, systemic administration of IL-15 increases the priming of Ag-specific CD8 + T cells (6). Unlike a large majority of cytokines, IL-15 can be presented by an APC that concomitantly expresses IL-15 and IL15Ra to an IL-15Rb/g-expressing cell.…”

Nicotinic acid inducing G0/G1 cell cycle arrest and apoptosis in Ehrlich ascites carcinoma cells in vivo

“…The cell pellet was resuspended in 5 ml of ACK lysing buffer, incubated for 5 min at room temperature, and then diluted with 45 ml of PBS; the cell suspension was centrifuged at 200 x g for 10 min at room temperature, and the supernatant was discarded. The cell pellet was resuspended in PBS and filtered through 45 μm cell strainer then cells were counted using a hemocytometer with trypan blue dye exclusion (Rubinstein et al, 2002).…”