CD40 ligand‐expressing recombinant vaccinia virus promotes the generation of CD8⁺ central memory T cells

Abstract

Central memory CD8 + T cells (T CM ) play key roles in the protective immunity against infectious agents, cancer immunotherapy, and adoptive treatments of malignant and viral diseases. CD8+ T CM cells are characterized by specific phenotypes, homing, and proliferative capacities. However, CD8 + T CM -cell generation is challenging, and usually requires CD4 + CD40L + T-cell "help" during the priming of naïve CD8 + T cells. We have generated a replication incompetent CD40 ligand-expressing recombinant vaccinia virus (rVV40L) to promote the differentiation of human naïve CD8 + T cells into T CM specific for viral and tumor-associated antigens. Soluble CD40 ligand recombinant protein (sCD40L), and vaccinia virus wild-type (VV WT), alone or in combination, were used as controls. Here, we show that, in the absence of CD4 + T cells, a single "in vitro" stimulation of naïve CD8 + T cells by rVV40L-infected nonprofessional CD14 + antigen presenting cells promotes the rapid generation of viral or tumor associated antigen-specific CD8 + T cells displaying T CM phenotypic and functional properties. These observations demonstrate the high ability of rVV40L to fine tune CD8 + mediated immune responses, and strongly support the use of similar reagents for clinical immunization and adoptive immunotherapy purposes.Keywords: Antigen presenting cells r Central memory T cells r CD40-CD40L r CD4 + T cells r CD8 + T cells r Immunological memory r Vaccinia virus Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionGeneration of immunological memory represents a key tenet of the adaptive immune system. Memory T cells display the exquisite Correspondence: Dr. Paul Zajac e-mail: paul.zajac@usb.ch ability to respond to previously experienced antigens with clonal expansion and with the rapid elicitation of multiple effector function [1]. However, the origin of memory CD8 + T cells is still debated, particularly concerning the relationship between effector and memory cells [2].Current understanding is consistent with the "one cell, multiple fates" model postulating that memory and effector T cells C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2016. 46: 420-431 Immunomodulation 421 may arise from single naïve CD8 + T-cell precursor undergoing asymmetric division originating two daughter cells with different cell fates [3]. Alternatively, a linear differentiation model proposes that memory CD8 + T lymphocytes may derive from effector cells surviving the contraction phase of the primary immune response [4]. Memory compartment encompasses lymphocyte subpopulations characterized by different phenotypes, functional properties, and anatomic locations. Two main subsets, central (T CM ) and effector memory (T EM ) lymphocytes, displaying a differential expression of homing and chemokine receptors have consistently been identified [5,6].Notably, T CM are characterized by high proliferative potential in response to antigen stimulation and...

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“…þ T cells following 72-hour culture by flow cytometry (28). IFNg release in culture supernatants was assessed by using commercial ELISA Kits (BD Biosciences).…”

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“…Thus, their recruitment might represent a critical step in the elicitation of antitumor immune responses. [28][29][30] CXCR3 chemokine receptor is expressed in CD8+ lymphocytes, and, preferentially, in "central memory" T cells, characterized by marked antitumor potential 17,31 (Supplementary Figure 4a). While CXCR3 ligands include CXCL9, CXCL10, and CXCL11, the main role in CD8+ T cells recruitment has been attributed to CXCL10.…”

“…Due to these characteristics and its safety, VV has been used in recombinant form (rVV) in a variety of cancer immunotherapy protocols. [14][15][16][17][18] In particular, rVVs have successfully been used to induce T-cell responses specific for tumor-associated antigens (TAAs) in patients bearing cancers of different histological origins. 15,18 Moreover, rVVs have also been used as oncolytic reagents upon systemic or intratumoral administration.…”

“…20 In previous investigations, we have shown that a replicationincompetent rVV encoding multiple TAA-derived epitopes and CD80 and CD86 co-stimulatory molecules efficiently induced specific CTL responses in patients with advanced melanoma. 18,21 More recently, we constructed an rVV encoding CD40L (rVV40L) and reported its ability to exquisitely promote the expansion of human "central memory" CD8+ T cells 17 in replicationincompetent form. These studies prompted us to explore the possibility of using this non-lytic reagent to elicit the multiplicity of antitumor effects associated with CD40 triggering.…”