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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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 1

Isolation and gene marking of TCM- and TEM-derived CMV-specific CD8+ T cell clones for adoptive transfer.

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Isolation and gene marking of TCM- and TEM-derived CMV-specific CD8+ T c...
(A) CMV IE-specific T cells are present in TCM and TEM subsets of CD8+ peripheral blood lymphocytes. PBMCs from macaque 02258 were stained with mAbs to CD28, Fas, and CD8 to identify CD28+CD8+Faslo TN, CD28+CD8+Fashi TCM, and CD28–CD8+Fashi TEM fractions (left panel) and assayed by cytokine flow cytometry after stimulation with a CMV peptide (right panels). (B) Sorted CD62L+CD28+CD8+Faslo TN (top panel), CD62L+CD28+CD8+ Fashi TCM (middle panel), and CD62L–CD28–CD8+Fashi TEM (lower panel) T cells were stimulated with autologous CMV IE peptide-pulsed monocytes and assayed for cytolytic activity against peptide-pulsed (filled triangles) or unpulsed target cells (open circles). (C) Isolation of TCM- and TEM-derived CMV-specific CD8+ T cell clones. CD8+CD62L– and CD8+CD62L+ T cell subsets were cultured with peptide-pulsed monocytes. At day 7, T cell clones were isolated by limiting dilution, transduced to express ΔCD19 or CD20, and expanded for adoptive transfer. (D) Design of the retroviral vector constructs. MPSV-LTR, myeloproliferative sarcoma virus retroviral long terminal repeat; ψ+, extended packaging signal; PRE, woodchuck hepatitis virus posttranscriptional regulatory element; ΔCD19, truncated macaque CD19 cDNA; CD20, full-length macaque CD20 cDNA. (E) Selection of ΔCD19- and CD20-modified CD8+ T cell clones. Transduced T cells were enriched for ΔCD19 or CD20 expression using immunomagnetic beads and analyzed by flow cytometry to assess purity (right panels). Unmodified T cells (left panels) served as control. The percentages of CD8+ T cells positive for CD19 or CD20 are indicated.