Modeling the dynamics of neonatal CD8+ T-cell responses.

Abstract

Neonates are particularly susceptible to a number of infections, and the neonatal CD8+ T cell response demonstrates differences in both the phenotype and magnitude of responses to infection compared with adults. However, the underlying basis for these differences is unclear. We have used a mathematical modeling approach to analyze the dynamics of neonatal and adult CD8+ T cell responses following in vitro stimulation and in vivo infection, which allows us to dissect key cell-intrinsic differences in expansion, differentiation and memory formation. We found that neonatal cells started dividing 8 hrs earlier and proliferated at a faster rate (0.077 day−1 vs 0.105 day−1) than adult cells in vitro. In addition, neonatal cells also differentiated more rapidly, as measured by the loss in CD62L and Ly6C expression. We extended our mathematical modeling to analysis of neonatal and adult CD8+ T cells responding in vivo and demonstrated that neonatal cells divide more slowly than adult cells after day 4 post-infection. However, neonatal cells differentiate more rapidly, up-regulating more KLRG-1 per division than adult cells (20% vs. 5%). The dynamics of memory formation were also found to be different, with neonatal effector cells showing increased death (1.0 day−1 vs. 2.45 day−1). Comparison of the division of human cord blood and adult naïve cells stimulated in vitro showed more division in cord blood derived cells, consistent with the observations in mice. This work highlights differences of the cell-intrinsic division and differentiation program in neonatal CD8+ T cells.