Identification of Nascent Memory CD8 T Cells and Modeling of Their Ontogeny

Abstract

Primary immune responses generate short-term effectors and long-term protective memory cells. The delineation of the genealogy linking naive, effector, and memory cells has been complicated by the lack of phenotypes discriminating effector from memory differentiation stages. Using transcriptomics and phenotypic analyses, we identify Bcl2 and Mki67 as a marker combination that enables the tracking of nascent memory cells within the effector phase. We then use a formal approach based on mathematical models describing the dynamics of population size evolution to test potential progeny links and demonstrate that most cells follow a linear naive→early effector→late effector→memory pathway. Moreover, our mathematical model allows long-term prediction of memory cell numbers from a few early experimental measurements. Our work thus provides a phenotypic means to identify effector and memory cells, as well as a mathematical framework to investigate their genealogy and to predict the outcome of immunization regimens in terms of memory cell numbers generated.

Towards multiscale modeling of the CD8+ T cell response to viral infections

“…A similar differentiation pattern was also found in CD8 + T cells in humans after vaccination (Akondy et al, ). While this does not rule out fate determination into effector and memory cells early in the differentiation process, it presents strong evidence of memory cells arising from effector cells, supporting the pathway proposed by Crauste et al ().…”

Three-Compartment Model of CAR T-cell Immunotherapy

“…They undergo an expansion due to proliferation at a rate φ, and have half-life 1/µT. According to the linear progression model described in [11,20,51], they quickly differentiate at a rate ρ into long-term memory T cells, which are assumed to provide long lasting protection to the specific tumor/antigen. This means that at any future time in which memory cells come into contact with same tumor cells, memory T cells are able to rapidly be converted into effectors T cells, readily activated to prevent tumor progression.…”

“…Memory T cells CM form the immunological memory, a key dynamic of the adaptive immune system [11,51]. Since we are dealing with immunodeficient mice, they are formed exclusively from differentiation of CAR T cells at a rate ρ.…”

“…Recent experimental studies have investigated the relationship between immunotherapy with CAR T cells and the development of immunological memory in cancer [42,11]. Ruella et al [42] evaluated the immunotherapy with CAR T 123 cells against a Hodgkin's Lymphoma and the response to a challenge in immunodeficient NSG mice.…”

“…Mathematical models have contributed to the understanding of the mechanisms involved in immunotherapy [11,4,32,15,33], confronting hypotheses and testing different settings. Some models are used to evaluate the role of immunotherapy in tumor growth [47,30], while others aim to analyze the combination of therapies to potentiate response [14].…”