Clonal expansion determines CD8⁺ T cell phenotype in vivo.
by
Timothy Schlub
University of New South Wales, Australia
Coauthors: Vanessa Venturi (University of New South Wales, Australia) Katherine Kedzierska (University of Melbourne, Australia) Cameron Wellard (The Walter and Eliza Hall Institute, Australia) Peter Doherty (University of Melbourne, Australia) Stephen Turner (University of Melbourne, Australia) Ruy Ribeiro (Los Alamos National Laboratory, USA) Philip Hodgkin (The Walter and Eliza Hall Institute, Australia) Miles Davenport (University of New South Wales, Australia)

The CD8⁺ “killer” T cell response to infection involves extensive T cell division and differentiation. Expression of the adhesion molecule CD62L is high on naïve cells that have not seen virus, and rapidly down regulated on the surface of the majority ( ~ 90%) of cells present in the ‘effector’ phase of acute infection. Various models have been proposed to explain the progression of the cellular differentiation of this system. We demonstrate that the extent of CD62L down-regulation is positively correlated with clone size in vivo, suggesting that the number of divisions a T cell has undergone may determine its levels of CD62L expression (phenotype). We develop a mathematical model of division-linked CD62L differentiation that reproduces the experimental population kinetics and phenotype during the acute infection. The model is subsequently used to simulate a heterogeneous clonal population responding to influenza virus infection and generating a repertoire of responding clonotypes (T cell receptor sequences that enable recognition of viral peptides). The model demonstrates that many of the features of the CD62L^hi and CD62L^lo T cell receptor repertoire observed in vivo can be explained with a simple mechanism of ‘division-linked differentiation’. We further demonstrate that division-linked CD62L differentiation adequately describes our experimental kinetic and repertoire data. Moreover, this is robust in terms of the mathematical description used for cell division, or the parameters used to distinguish different clonotypes.

Date received: May 14, 2008