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Secretory Phospholipase A2 (sPLA2) represents a diverse class of roughly 20 enzymes, 12 of which have been identified in humans. These isoforms can be distinguished based on their tissue distribution, structure, and regulation. These differences in structure between the isoforms lead to the question does the enzyme's ability to respond to physical changes in the membrane during apoptosis governed by structure. S49 cell apoptosis was initiated by treatment with either the glucocorticoid dexamethasone (6–48 h) or with the calcium ionophore, ionomycin. The rates of hydrolysis were compared with each treatment condition for various concentrations of snake venom and human groups (hG) IIA, V, and X isoforms. The data were analyzed using a model that explicitly evaluates both the adsorption of enzyme to the membrane surface (step 1) and subsequent binding of substrate to the active site (step 2). Increased hydrolysis during apoptosis appeared to reflect step 2 for both the snake venom and the hGX enzymes. In contrast, apoptosis promoted step 1 for hGV. For hGIIA, the kinetics were more complex suggesting additional mechanisms beyond these two steps. These observations are rationalized in terms of the structure of the various isozymes and physical changes during apoptosis, including reduction in the strength of lipid/neighbor interactions and increased bilayer surface charge.

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Human natural killer (NK) cells are found in virtually all tissues where they act as a first line defense against malignant and virally infected cells. The development of NK cells from CD34+ hematopoietic progenitors is a complex process that involves navigating through different microenvironments and requires contact-dependent interactions with stromal cells. The molecular mediators of NK cell developmental subset trafficking, cell-cell interactions, and maturation have not been fully characterized. This thesis presents 3 studies that aim to uncover contact-dependent interactions that drive human NK cell development. Chapter 2 focuses on defining the adhesome profile of human NK cells from in vitro derived populations, tonsil, and peripheral blood. This study reveals that the tissue origin and developmental stage of NK cells influence the expression of adhesome-associated genes and proteins, as well as the content of cortical actin, which suggests a link between adhesome expression and actin regulation in NK cells. Chapter 3 presents the first comprehensive study on human NK cell development in pediatric tonsil using cyclic immunofluorescence microscopy and imaging mass cytometry. We reveal that NK cell subset localization and interactions are dependent on NK cell developmental stage and tissue residency. Chapter 4 demonstrates that neural cell adhesion molecule (NCAM) on stromal cells promotes maintenance of a mesenchymal-like state and subsequently the survival and proliferation of human NK cell precursors. Overall, this thesis provides new insights on previously unknown mediators of NK cell contact-dependent interactions and unveils the first road map of in situ NK cell development.

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