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Comparison of naive and central memory derived CD8⁺ effector cell engraftment fitness and function following adoptive transfer.

ABSTRACT: Human CD8⁺ effector T cells derived from CD45RO⁺CD62L⁺ precursors enriched for central memory (T_CM) precursors retain the capacity to engraft and reconstitute functional memory upon adoptive transfer, whereas effectors derived from CD45RO⁺CD62L^- precursors enriched for effector memory precursors do not. Here we sought to compare the engraftment fitness and function of CD8⁺ effector T cells derived from CD45RA⁺CD62L⁺ precursors enriched for naïve and stem cell memory precursors (T_N/SCM) with that of T_CM. We found that cytotoxic T cells (CTLs) derived from T_CM transcribed higher levels of CD28, FOS, INF?, Eomesodermin (Eomes), and lower levels of BCL2L11, maintained higher levels of phosphorylated AKT, and displayed enhanced sensitivity to the proliferative and anti-apoptotic effects of ?-chain cytokines compared to CTLs derived from T_N/SCM. Higher frequencies of CTLs derived from T_CM retained CD28 expression and upon activation secreted higher levels of IL-2. In NOD/Scid IL-2R?C^null mice, CD8⁺ T_CM derived CTLs engrafted to higher frequencies in response to human IL-15 and mounted robust proliferative responses to an immunostimulatory vaccine. Similarly, CD8⁺ T_CM derived CD19CAR⁺ CTLs exhibited superior antitumor potency following adoptive transfer compared to their CD8⁺ T_N/SCM derived counterparts. These studies support the use of T_CM enriched cell products for adoptive therapy of cancer.

SUBMITTER: Wang X

PROVIDER: S-EPMC4760301 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Comparison of naïve and central memory derived CD8+ effector cell engraftment fitness and function following adoptive transfer.

Wang Xiuli X Wong ChingLam W CW Urak Ryan R Taus Ellie E Aguilar Brenda B Chang Wen-Chung WC Mardiros Armen A Budde Lihua E LE Brown Christine E CE Berger Carolina C Forman Stephen J SJ Jensen Michael C MC

Oncoimmunology 20150820 1

Human CD8+ effector T cells derived from CD45RO+CD62L+ precursors enriched for central memory (TCM) precursors retain the capacity to engraft and reconstitute functional memory upon adoptive transfer, whereas effectors derived from CD45RO+CD62L- precursors enriched for effector memory precursors do not. Here we sought to compare the engraftment fitness and function of CD8+ effector T cells derived from CD45RA+</sup ...[more]

PMID: 26942092

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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.

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Comparison of naive and central memory derived CD8⁺ effector cell engraftment fitness and function following adoptive transfer.

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Comparison of naïve and central memory derived CD8<sup>+</sup> effector cell engraftment fitness and function following adoptive transfer.

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Dataset Information

Comparison of naive and central memory derived CD8+ effector cell engraftment fitness and function following adoptive transfer.

Publications

Comparison of naïve and central memory derived CD8<sup>+</sup> effector cell engraftment fitness and function following adoptive transfer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Comparison of naive and central memory derived CD8⁺ effector cell engraftment fitness and function following adoptive transfer.