Adoptive transfer of effector CD8+ T cells derived from central memory cells establishes persistent T cell memory in primates
Carolina Berger, … , Carole Elliott, Stanley R. Riddell
Carolina Berger, … , Carole Elliott, Stanley R. Riddell
Published December 3, 2007
Citation Information: J Clin Invest. 2008;118(1):294-305. https://doi.org/10.1172/JCI32103.
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Research Article Immunology

Adoptive transfer of effector CD8+ T cells derived from central memory cells establishes persistent T cell memory in primates

Abstract

The adoptive transfer of antigen-specific T cells that have been expanded ex vivo is being actively pursued to treat infections and malignancy in humans. The T cell populations that are available for adoptive immunotherapy include both effector memory and central memory cells, and these differ in phenotype, function, and homing. The efficacy of adoptive immunotherapy requires that transferred T cells persist in vivo, but identifying T cells that can reproducibly survive in vivo after they have been numerically expanded by in vitro culture has proven difficult. Here we show that in macaques, antigen-specific CD8+ T cell clones derived from central memory T cells, but not effector memory T cells, persisted long-term in vivo, reacquired phenotypic and functional properties of memory T cells, and occupied memory T cell niches. These results demonstrate that clonally derived CD8+ T cells isolated from central memory T cells are distinct from those derived from effector memory T cells and retain an intrinsic capacity that enables them to survive after adoptive transfer and revert to the memory cell pool. These results could have significant implications for the selection of T cells to expand or to engineer for adoptive immunotherapy of human infections or malignancy.

Authors

Carolina Berger, Michael C. Jensen, Peter M. Lansdorp, Mike Gough, Carole Elliott, Stanley R. Riddell

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Figure 4

CD8+ TCM-derived clones exhibit improved survival in IL-15 in vitro and decreased apoptosis in vivo.

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CD8+ TCM-derived clones exhibit improved survival in IL-15 in vitro and ...
(A) Aliquots of TEM- and TCM-derived clones used for adoptive transfer were plated at the end of a 14-day stimulation cycle in medium alone (open triangles), IL-2 (1 ng/ml) (filled diamonds), or IL-15 (1 ng/ml) (filled squares), and viability was determined using Trypan blue dye exclusion. Data are representative of 13 TCM- and 11 TEM-derived clones from 3 macaques. (B) Expression of IL-15Rα, IL-2Rβ, and IL-2Rγ on TCM-derived (bold lines) and TEM-derived (black lines) clones transferred to macaque 02269 was measured by flow cytometry on days 13–14 after stimulation (dotted lines, isotype control mAb). Data are representative of clones administered to macaques 02258 and A99171. (C) Bcl-xl and Bcl-2 expression on 3 TEM-derived (white bars) and TCM-derived (gray bars) clones transferred to macaques 02269, 02258, and A99171 analyzed 14 days after stimulation. Mean ± SD of the MFI is shown on the y axis. (D) Apoptosis of TEM- and TCM-derived clones in vivo. The percent of CD19+CD8+ T cells in PBMCs that were Annexin V+ and/or PI+ 1 day after infusion of ΔCD19+ TEM-derived or TCM-derived T cell clones to macaque A99171 was determined directly and after 24-hour culture. Samples were gated on CD8+CD19– (white bars) and CD8+CD19+ T cells (black bars). Hatched bars show the T cells used for infusion. (E) Persistence and migration of TEM-derived and TCM-derived TE clones in macaque A99171. PBMC, BM, and LN cells obtained at indicated times were analyzed by flow cytometry to detect transferred CD19+CD8+ TE in samples gated on CD3+CD8+.