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.

Human peripheral blood and bone marrow Epstein–Barr virus‐specific T‐cell repertoire in latent infection reveals distinct memory T‐cell subsets

“…However, IFN-g-producing T cells are generally considered as differentiated and short-lived effector memory or effector T cells and do not correlate with long-term immunity as shown in a murine OVA-model [30]. Central memory T cells, which are typically characterized by IL-2 production [31], were shown in several infectious models, including CMV in primates [32] and in lymphocytic choriomeningitis virus (LCMV) in the murine system [33], to mediate long-term immunoprotection and to be associated with superior disease control as compared to effector memory T cells. Initially memory T cells were characterized based on the expression of the CC-chemokine receptor 7 (CCR7) as CCR7 -effector and CCR7 1 central memory T cells [31].…”

Viral-specific adoptive immunotherapy after allo-SCT: the role of multimer-based selection strategies

“…Stimulation of antigen-specific CD8 þ T cells using extensive cellular culture under specific antigenic stimulation does not induce a homogeneous cellular product but a high number of subpopulations with diverse differentiation status, different phenotypes and functional and migratory capacities. 16 Thus, Berger et al 17 showed that antigenspecific CD8 þ T E derived from a subset of memory T cells named effector memory (T EM ) survive for only a short period after adoptive transfer, and failed to home to lymph nodes or BM.…”

“…Therefore, selection of T CM cells would ensure that after adoptive transfer the cellular product consisting of T E cells would be able to persist durably in vivo and revert to the memory pool. 17,18 However, acquisition of terminal effector properties and an increase in cytotoxic activity in vitro generate less effective cells at triggering disease regression in vivo. 19 Thus, the more-differentiated cells, with superior in vitro antitumor properties, are less capable of mediating tumor regression upon adoptive transfer.…”

Progress and prospects: graft-versus-host disease

“…Several groups are currently exploiting gene transfer technologies to increase the life span and potential expansion of infused lymphocytes, 75 thus producing genetically modified tumor-specific T cells capable on one hand to target and eliminate tumor cells in vivo (effectors), and, on the other, to provide a continuous and persistent surveillance against the reappearance of tumor cells (central memory cells). This goal might be either achieved by expressing homeostatic cytokines, 76 or cognate receptors 77 into T lymphocytes, or by gene transfer and expansion of selected T-cell sub-populations with retroviral and lentiviral vectors.…”