Theoretical Biology, Utrecht University

http://theory.bio.uu.nl/vitaly/

A quantitative framework for estimation of per capita killing rates of antigen-specific CD8 T cells in vivo: a LCMV case

Despite recent advances in immunology, several key immunological parameters determining virus dynamics in infected hosts remain largely unknown. For example, the rate at which effector and memory CD8 T cells specific to a particular antigen clear virus-infected cells in vivo, is hardly known for any viral infection. We propose a new framework to quantify CD8 T cell mediated killing of virus-infected or peptide-pulsed target cells in vivo. We develop a specific model for a short term T cell mediated killing of targets in a mouse spleen. As an example of the new technique, we reanalyze recently published data on killing of peptide-pulsed splenocytes by cytotoxic T lymphocytes and memory CD8 T cells specific to NP396 and GP276 epitopes of LCMV. Using this novel framework, we estimate that the half-life time of the NP396- and GP276-pulsed targets in the spleens of acutely infected mice is 2 and 6 minutes, respectively, while in the spleens of memory mice, half of NP396- and GP276-expressing targets are eliminated in 49 minutes and 1.3 hour, respectively. While as a population, effectors are highly effective at eliminating peptide-pulsed cells, on average they kill less than one cell per day. In contrast, each memory CD8 T cell can eliminate on average five of pulsed targets per day. We also show that killing of peptide-pulsed targets in neither purely frequency- or density-dependent, and on the per cell basis, the killing efficacy of LCMV-specific memory and effector CD8 T cells is similar.

Instituto Gulbenkian de Ciência (Theoretical Immunology)

Diversity and shape of peripheral effector and regulatory T cell repertoires

A healthy immune system involves a fine balance between effector T cells (Teffs) that mount immune responses, and regulatory T cells (Tregs) that suppress them. When this balance is perturbed immunopathologies arise. Understanding this balance requires to know how diverse are the repertoires of Teffs and Tregs and how they relate to each other. A too large intersection between the repertoires could lead to deleterious inhibition of specific immune responses against harmful microorganisms, while a too small overlap may open the way to autoimmune responses. Here we address this issue by re-analyzing available data (e.g., Immunity, 2004, 21:267-277). Our results show that both Tregs and Teffs are similar diverse with Lognormal abundances distributions. Moreover, the repertoires might be the same with abundances being at best positively correlated. The causes and the implications of these results need further investigation.