![]() The anionic phospholipids, phosphatidylserine (PS) and phosphatidylethanolamine, are maintained on the inner leaflet, while phosphatidylcholine and sphingomyelin primarily compose the outer leaflet ( 5). The eukaryotic plasma membrane is carefully regulated to maintain an asymmetric distribution of phospholipids under homeostatic conditions. High concentrations of IL-2 present during antigen receptor activation is associated with the development of a short-lived, terminal effector cell phenotype, while in contrast, low concentrations of IL-2 are associated with the formation of long-lived memory cells ( 4). Moreover, it is well understood that the strength of IL-2 signaling influences cell fate through activation of different transcriptional programs. IL-2 signaling activates several key pathways including phosphorylated signal transducer and activator of transcription 5 (pSTAT5), mitogen-activated protein kinase (MapK)/extracellular signal-related kinase (Erk), and phosphoinositol-3-kinase (PI3K)/Akt pathways to promote survival, proliferation and differentiation of activated T cells ( 4). IL-2 is a 15.5 kDa cytokine primarily produced by T cells as well as dendritic cells early in T cell activation and acts locally through autocrine or paracrine binding to the IL-2 receptor (IL-2R) ( 3). The local cytokine milieu present during T cell priming is commonly referred to as “signal 3” and helps skew CD4 and CD8 T cells to the appropriate effector cell phenotype to achieve full T cell activation ( 2). T cell priming against foreign antigens is a complex process requiring the integration of signal 1, through pMHC, and signal 2, through CD28 co-stimulation ( 2). ![]() Physiologically, CD8 T cells function to recognize and remove infected and malignant cells through antigen receptor mediated recognition of peptides presented on MHC class I molecules (pMHC). CD8 and CD4 T cells are an important arm of the adaptive immune system and the T cell repertoire is incredibly diverse with the potential for 10 7-10 8 unique T cell receptors poised to respond to a pathogenic challenge ( 1). The adaptive immune system is critical for defense against pathogens and providing long-term immunological protection. ![]() Our data supports the use of AnnV-IL2 to modulate antigen-specific T cell immunity and demonstrates that the PS-AnnV axis is a feasible mechanism to target diverse cargo to CD8 T cells. Importantly, upon antigen rechallenge, AnnV-IL2 treatment mice demonstrated a stronger secondary expansion, indicating durability of AnnV-IL2 mediated responses. In vivo, AnnV-IL2 promotes robust expansion of antigen-specific cells capable of interferon gamma (IFNγ) production when administered following peptide vaccination. Consequently, AnnV-IL2 proved to be significantly more effective at enhancing T cell activation compared to recombinant IL-2. In vitro analysis revealed that AnnV-IL2 is able to specifically bind PS on the T cell surface following TCR stimulation. This was accomplished using a novel chimeric fusion protein of annexin V and interleukin 2 (AnnV-IL2). To expand these studies, we aimed to exploit TCR activation driven PS exposure as a target to deliver cytokine, namely interleukin-2 (IL-2), to the surface of CD8 T cells. Annexin V (AnnV) is a protein known to bind PS with high affinity and has been effectively utilized to anchor antigen to the surface of CD8 T cells. Independent of apoptosis, PS is redistributed to the surface of CD8 T cells in response to TCR-mediated activation. The phospholipid phosphatidylserine (PS) is naturally maintained on the cytoplasmic side of the plasma membrane. ![]()
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