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Human effector CD8+ T cells derived from naive rather than memory subsets possess superior traits for adoptive immunotherapy.

ABSTRACT: Cluster of differentiation (CD)8(+) T cells exist as naive, central memory, and effector memory subsets, and any of these populations can be genetically engineered into tumor-reactive effector cells for adoptive immunotherapy. However, the optimal subset from which to derive effector CD8(+) T cells for patient treatments is controversial and understudied. We investigated human CD8(+) T cells and found that naive cells were not only the most abundant subset but also the population most capable of in vitro expansion and T-cell receptor transgene expression. Despite increased expansion, naive-derived cells displayed minimal effector differentiation, a quality associated with greater efficacy after cell infusion. Similarly, the markers of terminal differentiation, killer cell lectin-like receptor G1 and CD57, were expressed at lower levels in cells of naive origin. Finally, naive-derived effector cells expressed higher CD27 and retained longer telomeres, characteristics that suggest greater proliferative potential and that have been linked to greater efficacy in clinical trials. Thus, these data suggest that naive cells resist terminal differentiation, or "exhaustion," maintain high replicative potential, and therefore may be the superior subset for use in adoptive immunotherapy.

SUBMITTER: Hinrichs CS

PROVIDER: S-EPMC3035075 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Human effector CD8+ T cells derived from naive rather than memory subsets possess superior traits for adoptive immunotherapy.

Hinrichs Christian S CS Borman Zachary A ZA Gattinoni Luca L Yu Zhiya Z Burns William R WR Huang Jianping J Klebanoff Christopher A CA Johnson Laura A LA Kerkar Sid P SP Yang Shicheng S Muranski Pawel P Palmer Douglas C DC Scott Christopher D CD Morgan Richard A RA Robbins Paul F PF Rosenberg Steven A SA Restifo Nicholas P NP

Blood 20101022 3

Cluster of differentiation (CD)8(+) T cells exist as naive, central memory, and effector memory subsets, and any of these populations can be genetically engineered into tumor-reactive effector cells for adoptive immunotherapy. However, the optimal subset from which to derive effector CD8(+) T cells for patient treatments is controversial and understudied. We investigated human CD8(+) T cells and found that naive cells were not only the most abundant subset but also the population most capable of ...[more]

PMID: 20971955

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Project description:Cytomegaloviruses (CMVs) are host species-specific in their replication. It is a hallmark of all CMVs that productive primary infection is controlled by concerted innate and adaptive immune responses in the immunocompetent host. As a result, the infection usually passes without overt clinical symptoms and develops into latent infection, referred to as "latency". During latency, the virus is maintained in a non-replicative state from which it can reactivate to productive infection under conditions of waning immune surveillance. In contrast, infection of an immunocompromised host causes CMV disease with viral multiple-organ histopathology resulting in organ failure. Primary or reactivated CMV infection of hematopoietic cell transplantation (HCT) recipients in a "window of risk" between therapeutic hemato-ablative leukemia therapy and immune system reconstitution remains a clinical challenge. Studies in the mouse model of experimental HCT and infection with murine CMV (mCMV), followed by clinical trials in HCT patients with human CMV (hCMV) reactivation, have revealed a protective function of virus-specific CD8 T cells upon adoptive cell transfer (AT). Memory CD8 T cells derived from latently infected hosts are a favored source for immunotherapy by AT. Strikingly low numbers of these cells were found to prevent CMV disease, suggesting either an immediate effector function of few transferred cells or a clonal expansion generating high numbers of effector cells. In the murine model, the memory population consists of resting central memory T cells (TCM), as well as of conventional effector-memory T cells (cTEM) and inflationary effector-memory T cells (iTEM). iTEM increase in numbers over time in the latently infected host, a phenomenon known as 'memory inflation' (MI). They thus appeared to be a promising source for use in immunotherapy. However, we show here that iTEM contribute little to the control of infection after AT, which relies almost entirely on superior proliferative potential of TCM.

Dataset Information

Human effector CD8+ T cells derived from naive rather than memory subsets possess superior traits for adoptive immunotherapy.

Publications

Human effector CD8+ T cells derived from naive rather than memory subsets possess superior traits for adoptive immunotherapy.

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