Clonal stochasticity in early NK cell response to mouse cytomegalovirus is generated by mature subsets of varying proliferative ability

Abstract

AbstractNatural killer (NK) cells from C57BL/6 mice respond to mouse cytomegalovirus (MCMV) infection within the first week of the infection by proliferating and differentiating in an antigen-specific manner. This antigen-specific expansion response is common in adaptive immune cells such as CD8+ T cells, but not innate immune cells like NK cells. However, NK cells and CD8+ T cells share a variety of similar behaviors in antigen-specific expansion. For example, clones derived from single cells are largest during expansion when they are primarily CD27-for NK cells and CD62L-for T cells, phenotypes derived from precursor CD27+ and CD62L+ cells, respectively. Here we determined the mechanistic rules involving proliferation, cell death, and differentiation of endogenous and adoptively transferred NK cells in the expansion phase of the response to MCMV infection. We found that the interplay between cell proliferation and cell death of mature CD27-NK cells and a highly proliferative CD27-Ly6C-mature subtype and intrinsic stochastic fluctuations in these processes play key roles in regulating the heterogeneity and population of the NK cells subtypes. Furthermore, we estimate rates for maturation of endogenous NK cells in homeostasis and in MCMV infection and found that only NK cell growth rates, and not differentiation rates, are appreciably increased by MCMV. Taken together, these results quantify the differences between the kinetics of NK cell antigen-specific expansion from that of CD8+ T cells and unique mechanisms that give rise to the observed heterogeneity in NK cell clones generated from single NK cells in the expansion phase.SignificanceNatural killer (NK) cells are classically defined as innate immune cells, but experiments show that mouse cytomegalovirus (MCMV) infection can cause NK cells to undergo antigen-specific proliferation and memory formation, similar to adaptive immune cells called CD8+ T cells. One shared behavior between CD8+ T cells and NK cells is clonal expansion, where a single stimulated cell proliferates rapidly to form a diverse population of cells. Using a combination of stochastic population dynamic models and data, we find that higher proliferation of a mature subtype, increased death of mature NK cells, and the presence of intrinsic stochastic fluctuations in these processes distinguish antigen specific NK cell expansion from that of CD8+ T cells.