CD27 costimulation contributes substantially to the expansion of functional memory CD8⁺T cells after peptide immunization

Abstract

Naive T cells require signals from multiple costimulatory receptors to acquire full effector function and differentiate to long-lived memory cells. The costimulatory receptor, CD27, is essential for optimal T-cell priming and memory differentiation in a variety of settings, although whether CD27 is similarly required during memory CD8 + T-cell reactivation remains controversial. We have used OVA and anti-CD40 to establish a memory CD8 + T-cell population and report here that their secondary expansion, driven by peptide and anti-CD40, polyI:C, or LPS, requires CD27. Furthermore, antigenic peptide and a soluble form of the CD27 ligand, CD70 (soluble recombinant CD70 (sCD70)), is sufficient for secondary memory CD8 + T-cell accumulation at multiple anatomical sites, dependent on CD80/86. Prior to boost, resting effector-and central-memory CD8 + T cells both expressed CD27 with greater expression on central memory cells. Nonetheless, both populations upregulated CD27 after TCR engagement and accumulated in proportion after boosting with Ag and sCD70. Mechanistically, sCD70 increased the frequency of divided and cytolytic memory T cells, conferred resistance to apoptosis and enabled retardation of tumor growth in vivo. These data demonstrate the central role played by CD27/70 during secondary CD8 + T-cell activation to a peptide Ag, and identify sCD70 as an immunotherapeutic adjuvant for antitumor immunity.Keywords: CD27 r CD70 r Memory r T cell r TLR r TNFRSF Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionT lymphocytes mediate immunity to infection and can protect against tumor growth. For full activation, T cells require TCR engagement and costimulatory signals provided predominantly Correspondence: Dr. Sarah L. Buchan e-mail: slb@soton.ac.uk through members of the Ig superfamily (e.g. CD28 and ICOS) and TNF receptor superfamily (TNFRSF; e.g. CD27 and 4-1BB). TNFRSF receptors signal via the NF-κB, MAPK, and PI3K pathways to facilitate cell cycle progression, upregulation of antiapoptotic Bcl-2 family members, secretion of cytokines, and expression of * These authors share co-authorship. * * These authors share senior co-authorship.C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2013. 43: 3314-3323 Immunomodulation 3315 cytokine receptors leading to improved T-cell survival and proliferation. The existence of multiple TNFRSF members allows for tight temporal and spatial control of T-cell activation, regulated in part by the expression patterns of the receptors and their ligands [1]. Unlike many TNFRSF receptors, CD27 is highly expressed on naive CD4 + and CD8 + T cells and is further upregulated after TCR engagement [2]. The only known ligand for CD27/CD70 exhibits limited expression at rest but is upregulated on DC and B cells within 24 h of incubation with anti-CD40 or TLR agonists [3][4][5]. CD27/CD70 is therefore well poised to contribute to early T-cell activation events. Indeed, CD27 signals a...

Stimulating CD27 to quantitatively and qualitatively shape adaptive immunity to cancer

“…CD27 stimulation significantly increases the magnitude of T cell responses to peptide or protein antigen in murine models [3••;17;60•] and synergizes with IFN-1 in both the expansion of effector CD8 + T cells and the subsequent development of CD8 + T cell memory. As the variegated influences of CD27 on effector and memory T cell development become more understood, there may be opportunities select regimens to support central, effector or tissue resident memory cells.…”

T Cell Vaccinology: Beyond the Reflection of Infectious Responses

“…These results stand in reasonably sharp contrast to the role of these receptors in a vaccine setting, where the blockade of CD27 produces dramatic (>10 fold) inhibition of the primary expansion of CD8 T cells [9–15, 45, 57–59]. Curiously, OX40 can serve as a reasonable substitute to support CD8+ T cell expansion to vaccination, but only in the developmental absence (KO animals) of CD27[12].…”

“…OX40 has a less obscure role in CD4 cell response to vaccination where both CD27 and OX40 signaling are required for peak responses in the WT host [45]. While we have studied this extensively in response to the combined innate/CD40 vaccine adjuvant, others, using a diversity of immunization platforms (adjuvants, in vitro derived DCs, etc) have observed a similar importance for CD27 in a vaccine-elicited T cell response [9–15, 45, 57–59]. In the majority of these systems, this CD27 dependency influences expansion, survival and programming of effectors and memory.…”

“…In contrast, IL-27 signaling appears to be required for the T cell responses to a host of subunit adjuvants [2], while the response to infectious challenge is either unaffected or even elevated in the absence of this cytokine [3, 4]. TNF receptor superfamily members expressed by T cells largely enhance various qualitative aspects of the T cell responses during infection [5–8], but instead dictate the quantitative magnitude of the response in subunit vaccine settings [9–15]. In short, the success or failure to produce a cellular response by subunit vaccination may be guided by different underlying mechanisms than those that govern infectious challenge.…”

Differential expression and function of CD27 in chronic lymphocytic leukemia cells expressing ZAP-70

“…CLL cells express both cell surface and soluble CD27 [20] and blocking the release of sCD27 using MMP-9 inhibitors induce higher levels of accessory molecules such as CD54, CD80 and CD95 [21]. Recent studies have confirmed functions for CD27 in T cell activation [22,23] and chronic myelogenous leukemia [24]; however, less data is available regarding CD27 function in normal B cells or CLL cells. One study using mouse models suggested a B cell intrinsic function of CD27 in germinal center responses [25].…”