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 agonist-based 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-27R?. 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.
While neddylation is known to activate cullin (CUL)-RING ubiquitin ligases (CRLs), its role in regulating T cell signaling is poorly understood. Using the investigational NEDD8 activating enzyme (NAE) inhibitor, MLN4924, we found that neddylation negatively regulates T cell receptor (TCR) signaling, as its inhibition increases IL-2 production, T cell proliferation and Treg development in vitro. We also discovered that loss of CUL neddylation occurs upon TCR signaling, and CRLs negatively regulate IL-2 production. Additionally, we found that tyrosine kinase signaling leads to CUL deneddylation in multiple cell types. These studies indicate that CUL neddylation is a global regulatory mechanism for tyrosine kinase signaling.
The objective of modern vaccine development is the safe generation of protective long-term immune memory, both prophylactic and therapeutic. Live attenuated vaccines generate potent cellular and humoral immunity [1-3], but numerous problems exist with these vaccines, ranging from production and storage issues to adverse reactions and reversion to virulence. Subunit vaccines are safer, more stable, and more amenable to mass production. However the protection they produce is frequently inferior to live attenuated vaccines and is typically confined to humoral, and not cellular immunity. Unfortunately, there are presently no subunit vaccines available clinically that are effective at eliciting cellular responses let alone cellular memory . This article will provide and overview of areas of investigation that we see as important for the development of vaccines with the capacity to induce robust and enduring cellular immune responses.
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