mRNA vaccination boosts S-specific T cell memory and promotes expansion of CD45RAint TEMRA-like CD8+ T cells in COVID-19 recovered individuals.

SARS-CoV-2 infection and mRNA vaccination both elicit spike (S)-specific T cell responses. To analyze how T cell memory from prior infection influences T cell responses to vaccination, we evaluated functional T cell responses in naive and previously infected vaccine recipients. Pre-vaccine S-specific responses are predictive of subsequent CD8+ T cell vaccine-response magnitudes. Comparing baseline with post-vaccination TCRß repertoires, we observed large clonotypic expansions correlated with the frequency of spike-specific T cells. Epitope mapping the largest CD8+ T cell responses confirms that an HLA-A∗03:01 epitope was highly immunodominant. Peptide-MHC tetramer staining together with mass cytometry and single-cell sequencing permit detailed phenotyping and clonotypic tracking of these S-specific CD8+ T cells. Our results demonstrate that infection-induced S-specific CD8+ T cell memory plays a significant role in shaping the magnitude and clonal composition of the circulating T cell repertoire after vaccination, with mRNA vaccination promoting CD8+ memory T cells to a TEMRA-like phenotype.

Seeing beyond the average cell: branching process models of cell proliferation, differentiation, and death during mouse brain development.

We develop a family of branching process models to study cerebral cortical development at the level of individual neural stem and progenitor cells (NS/PCs) and the neurons they produce. Population-level data about "the average NS/PC" is incorporated as constraints for exploring (i) heterogeneity in the proliferative neural cell types and (ii) variability in daughter cell fate decision making. Preliminary studies demonstrate this variability, generate testable hypotheses about heterogeneity, and motivate new experiments moving forward.

Mathematical modeling supports substantial mouse neural progenitor cell death.

BACKGROUND: Existing quantitative models of mouse cerebral cortical development are not fully constrained by experimental data. RESULTS: Here, we use simple difference equations to model neural progenitor cell fate decisions, incorporating intermediate progenitor cells and initially low rates of neural progenitor cell death. Also, we conduct a sensitivity analysis to investigate possible uncertainty in the fraction of cells that divide, differentiate, and die at each cell cycle. CONCLUSION: We demonstrate that uniformly low-level neural progenitor cell death, as concluded in previous models, is incompatible with normal mouse cortical development. Levels of neural progenitor cell death up to and exceeding 50% are compatible with normal cortical development and may operate to prevent forebrain overgrowth as observed following cell death attenuation, as occurs in caspase 3-null mutant mice.

Finite element simulations of acetylcholine diffusion in neuromuscular junctions.

A robust infrastructure for solving time-dependent diffusion using the finite element package FEtk has been developed to simulate synaptic transmission in a neuromuscular junction with realistic postsynaptic folds. Simplified rectilinear synapse models serve as benchmarks in initial numerical studies of how variations in geometry and kinetics relate to endplate currents associated with fast-twitch, slow-twitch, and dystrophic muscles. The flexibility and scalability of FEtk affords increasingly realistic and complex models that can be formed in concert with expanding experimental understanding from electron microscopy. Ultimately, such models may provide useful insight on the functional implications of controlled changes in processes, suggesting therapies for neuromuscular diseases.