IL-27 is required for shaping the magnitude, affinity distribution, and memory of T cells responding to subunit immunization

Abstract

An elusive goal of cellular immune vaccines is the generation of large numbers of antigen-specific T cells in response to subunit immunization. A broad spectrum of cytokines and cell-surface costimulatory molecules are known to shape the programming, magnitude, and repertoire of T cells responding to vaccination. We show here that the majority of innate immune receptor agonistbased vaccine adjuvants unexpectedly depend on IL-27 for eliciting CD4 + and CD8 + T-cell responses. This is in sharp contrast to infectious challenge, which generates T-cell responses that are IL-27-independent. Mixed bone marrow chimera experiments demonstrate that IL-27 dependency is T cell-intrinsic, requiring T-cell expression of IL-27Rα. Further, we show that IL-27 dependency not only dictates the magnitude of vaccine-elicited T-cell responses but also is critical for the programming and persistence of high-affinity T cells to subunit immunization. Collectively, our data highlight the unexpected central importance of IL-27 in the generation of robust, high-affinity cellular immune responses to subunit immunization.

Distinct Graft-Specific TCR Avidity Profiles during Acute Rejection and Tolerance

“…One possibility may be through Program Death-1/Program Death Ligand 1 (PD-1/PD-L1) signaling, because populations of T cells deficient in PD-1 expand more and have higher-avidity TCRs (Jiang et al, 2016). Another factor may be levels of interleukin (IL) 27, a cytokine that is produced by APCs and has been shown to play a role in the generation of high-avidity T cells (Pennock et al, 2014). Similarly, IL-12 produced by dendritic cells may also contribute to the generation of these cells (DeBenedette et al, 2008).…”

The Immunobiology of Interleukin-27

“…However, there are models in which even outside the competitive setting, IL-27 is required for optimal CD8 + T cell responses (60). A major advance in this area has been the finding that the ability of vaccines that include an adjuvant composed of agonistic anti-CD40 antibodies combined with TLR ligands to elicit CD4 + and CD8 + T cell responses depends on the ability of IL-27 to promote T cell survival (116). These studies are notable because in parallel experiments the authors have shown that IL-27 limits infection-induced CD8 + T cell responses.…”

T Cell Vaccinology: Beyond the Reflection of Infectious Responses

“…To date, there are only a few subunit vaccine platforms capable of producing this level of T cell expansion, one of which is a combination adjuvant stimulating both an innate receptor (such as a TLR) and CD40 (combined innate/CD40). Much like the B cell response, the use of either of these single adjuvants typically produces around 10–50,000 total antigen specific CD8+ T cells [2], a number that is non-protective with respect to T cell responses [13]. In contrast, after a single exposure, the combined innate/CD40 adjuvant can produce a similar number of antigen specific T cells (~1–3 million antigen specific T cells), and in the same time frame (7 days), as the infectious challenge [2, 10, 13, 44, 45].…”

“…Much like the B cell response, the use of either of these single adjuvants typically produces around 10–50,000 total antigen specific CD8+ T cells [2], a number that is non-protective with respect to T cell responses [13]. In contrast, after a single exposure, the combined innate/CD40 adjuvant can produce a similar number of antigen specific T cells (~1–3 million antigen specific T cells), and in the same time frame (7 days), as the infectious challenge [2, 10, 13, 44, 45]. As a result of the potency of this vaccine adjuvant, we and others [46–48] have spent years studying its underlying mechanisms in mice and have recently shown its capacity to produce robust CD8 and CD4 responses in non-human primates [49].…”

“…While infectious models have shown central roles for type I IFN and IL-12 for mediating T cell differentiation and memory formation, these cytokines are often dispensable in the T cell response to subunit vaccination [1]. 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].…”