![]() 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. 3Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, United States.2Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, United States.1Graduate Program in Immunology, Johns Hopkins University School of Medicine, Baltimore, MD, United States.Alana MacDonald 1,2, Brandon Lam 1,2, John Lin 2, Louise Ferrall 2, Yu Jui Kung 2, Ya Chea Tsai 2, T.-C.
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