Stimulation through very late antigen‐4 and ‐5 improves the multifunctionality and memory formation of CD8⁺ T cells

Abstract

T cells express multiple integrin molecules. The significance of signaling through these molecules on acquisition of T-cell effector functions and memory formation capacity remains largely unknown. Moreover, the impact of stimulation through these signals on the generation of T cells for adoptive immunotherapy has not been elucidated. In this study, using a recombinant fragment of fibronectin, CH-296, we demonstrated that stimulation via very late Ag (VLA)-4 and VLA-5 in human and BALB/c mouse CD8 + T cells, in combination with TCR stimulation, enhances effector multifunctionality and in vivo memory formation. Using TCR-transgenic mouse-derived CD8 + T cells expressing TCR specific for the syngeneic CMS5 fibrosarcoma-derived tumor Ag, we showed that stimulation by CH-296 improved the ability of tumor-specific CD8 + T cells to inhibit CMS5 tumor growth when adoptively transferred into hosts with progressing tumors. Improved antitumor effects were associated with decreased infiltration of Foxp3 + CD4 + Treg cells in tumors. These results suggest that stimulation via VLA-4 and VLA-5 modulates the qualities of effector T cells and could potentially increase the efficacy of adoptive therapy against cancer.Keywords: CD8 + T cells r Integrins r Multifunctionality r Tumor immunology r Very late antigen (VLA) Additional supporting information may be found in the online version of this article at the publisher's web-site Correspondence: Dr. Hiroaki Ikeda e-mail: hikeda@clin.medic.mie-u.ac.jp IntroductionT cells express a number of surface molecules that mediate cell-tocell interactions, as well as binding of cells to extracellular matrix proteins [1][2][3]. Several of these adhesion receptors belong to the β1 subfamily of integrin molecules, also known as very late Ag (VLA) molecules, which are characterized by at least nine α-chains C 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 1748 Hayato Hosoi et al. Eur. J. Immunol. 2014. 44: 1747-1758 that share a noncovalently linked β-chain. Some of these receptors function not only as adhesion molecules but also as transducers of signals in T cells [3][4][5][6]. Several laboratories have shown that binding of human or mouse T cells to fibronectin can induce proliferation via VLA-4 (α4β1) and/or VLA-5 (α5β1) [7][8][9]. Consistent with these reports, we have shown that exposure to CH-296 (RetroNectin), a recombinant human fibronectin fragment that contains the binding domains for VLA-4 and -5, in conjunction with stimulation with anti-CD3 mAbs, promotes T-cell expansion while preserving the CD45RA high CCR7 high phenotype [10]. These results prompted us to investigate whether stimulation via VLA-4 and -5 modulates not only expansion of T cells but also their effector functions and in vivo fates. Cytotoxic T lymphocytes (CTLs) play critical roles in controlling tumor cells [11,12], and the adoptive cell transfer of tumorreactive CTLs is a promising strategy for immunological intervention against cancer [12][13][14]. For clinical applications, T cells of de...

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