Inflammatory IL-15 is required for optimal memory T cell responses
Martin J. Richer, … , Steven M. Varga, John T. Harty
Martin J. Richer, … , Steven M. Varga, John T. Harty
Published August 4, 2015
Citation Information: J Clin Invest. 2015;125(9):3477-3490. https://doi.org/10.1172/JCI81261.
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Research Article Immunology

Inflammatory IL-15 is required for optimal memory T cell responses

Abstract

Due to their ability to rapidly proliferate and produce effector cytokines, memory CD8+ T cells increase protection following reexposure to a pathogen. However, low inflammatory immunizations do not provide memory CD8+ T cells with a proliferation advantage over naive CD8+ T cells, suggesting that cell-extrinsic factors enhance memory CD8+ T cell proliferation in vivo. Herein, we demonstrate that inflammatory signals are critical for the rapid proliferation of memory CD8+ T cells following infection. Using murine models of viral infection and antigen exposure, we found that type I IFN–driven expression of IL-15 in response to viral infection prepares memory CD8+ T cells for rapid division independently of antigen reexposure by transiently inducing cell-cycle progression via a pathway dependent on mTOR complex-1 (mTORC1). Moreover, exposure to IL-15 allowed more rapid division of memory CD8+ T cells following antigen encounter and enhanced their protective capacity against viral infection. Together, these data reveal that inflammatory IL-15 promotes optimal responses by memory CD8+ T cells.

Authors

Martin J. Richer, Lecia L. Pewe, Lisa S. Hancox, Stacey M. Hartwig, Steven M. Varga, John T. Harty

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Figure 7

Exposure to IL-15 prepares memory CD8+ T cells for rapid division following T cell receptor triggering and is required for optimal proliferation and protective capacity.

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Exposure to IL-15 prepares memory CD8+ T cells for rapid division follow...
(A) Proliferation profiles (CTV dilution) of enriched memory P14 cells with (blue lines) or without (red lines) pretreatment with recombinant murine IL-15. Cells were then stimulated with cognate peptide (gp33–41) as indicated. (B) Same experimental design shown in A for antigen-experienced (CD8+ CD45RO+) human CD8+ T cells with (blue lines) or without (red lines) pretreatment with recombinant human IL-15 and stimulation with plate-bound anti-CD3. (C) Proliferation of naive P14 Tg CD8+ T cells transferred into WT hosts (green line) or memory P14 cells transferred into WT (blue line) or Il15–/– hosts (red line) was measured by CFSE dilution on day 3 following LCMV-ARM infection. (D) Cumulative data (mean ± SEM) of the percentage of naive or memory P14 cells transferred to WT or Il15–/– hosts (as indicated) having undergone greater than 5 divisions on day 3 following infection with LCMV-ARM. (E) Viral burden in the inguinal lymph node on day 3 following LCMV clone 13 infection of mice receiving either no adoptive transfer (green squares) or an adoptive transfer of memory P14 cells with daily treatment with either rat IgG (blue triangles) or anti-CD122 (clone TM-β1) (red inverted triangles). Data in A are from more than 3 pooled mice and are representative of 2 independent experiments. Data in B are from 1 human donor and are representative of 2 experiments with different individual donors. Data in C–E are from at least 3 mice per group and are representative of at least 2 independent experiments. Data in D and E were analyzed by 1-way ANOVA with Tukey’s post-test of multiple comparisons.