Key Points• Activated NK cells display heterogeneity in their cytotoxic responses that justifies grouping them into 5 distinct classes of NK cells.• A subpopulation of particularly active "serial killer" NK cells deliver their lytic hits faster and release more perforin in each hit.

The Natural Killer (NK) cell population is composed of subsets of varying sizes expressing different combinations of inhibitory receptors for MHC class I molecules. Genes within the NK gene complex, including the inhibitory receptors themselves, seem to be the primary intrinsic regulators of inhibitory receptor expression, but the MHC class I background is an additional Modulating factor. In this paper, we have performed a parallel study of the inhibitory receptor repertoire in inbred mice of the C57Bl/6 background and in a cohort of 44 humans. Deviations of subset frequencies from the “product rule (PR),” i.e., differences between observed and expected frequencies of NK cells, were used to identify MHC-independent and MHC-dependent control of receptor expression frequencies. Some deviations from the PR were similar in mice and humans, such as the decreased presence of NK cell subset lacking inhibitory receptors. Others were different, including a role for NKG2A in determining over- or under-representation of specific subsets in humans but not in mice. Thus, while human and murine inhibitory receptor repertoires differed in details, there may also be shared principles governing NK cell repertoire formation in these two species.

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Summary Lyn, a Src-family protein tyrosine kinase expressed in B lymphocytes, contributes to initiation of BCR signaling and is also responsible for feedback inhibition of BCR signaling. Lyn-deficient mice have a decreased number of follicular B cells and also spontaneously develop a lupus-like autoimmunity. We used flow cytometric analysis, BrdU labeling, and our mathematical models of B cell population dynamics, to analyze how Lyn deficiency impacts B-cell maturation and survival. We found that Lyn-deficient transitional 1 (T1) cells develop normally, but T2 cells develop primarily from the T1 subset in the spleen and fail to also develop directly from bone marrow immature B cells. Lyn-deficient T2 cells either mature to the follicular B-cell type at a close to normal rate, or die in this compartment rather than access the T3 anergic subset. The ~40% of wild type follicular cells that were short-lived exited primarily by joining the T3 anergic subset, whereas the ~15% Lyn−/− follicular cells that were not long-lived had a high death rate and died in this compartment rather than entering the T3 subset. We hypothesize that exaggerated BCR signaling resulting from weak interactions with self-antigens is largely responsible for these alterations in Lyn-deficient B cells.

The activity of natural killer (NK) cells is regulated by various processes including education/licensing, priming, integration of positive and negative signals through an array of activating and inhibitory receptors, and the development of memory-like functionality. These processes are often very complex due to the large number of different receptors and signaling pathways involved. Understanding these complex mechanisms is therefore a challenge, but is critical for understanding NK cell regulation. Mathematical approaches can facilitate the analysis and understanding of complex systems. Therefore, they may be instrumental for studies in NK cell biology. Here we provide a review of the different mathematical approaches to the analysis of NK cell signal integration, activation, proliferation, and the acquisition of inhibitory receptors. These studies show how mathematical methods can aid the analysis of NK cell regulation.