Antigen-Stimulated CD4 T Cell Expansion Can Be Limited by Their Grazing of Peptide–MHC Complexes

Abstract

It was recently shown that the expansion of CD4+ T cells during a primary immune reaction to a peptide from cytochrome c decreases ∼0.5 log for every log increase in the number of cognate precursor cells, and that this remains valid over more than four orders of magnitude (Quiel et al. 2011. Proc. Natl. Acad. Sci. USA. 108: 3312–3317). This observed “power law” was explained by a mechanism where nondividing mature T cells inhibit the proliferation of less-differentiated cells of the same specificity. In this article, we interpret the same data by a mechanism where CD4+ T cells acquire cognate peptide-MHC (pMHC) complexes from the surface of APCs, thereby increasing the loss rate of pMHC. We show that a mathematical model implementing this “T cell grazing” mechanism, and having a T cell proliferation rate that is determined by the concentration of pMHC, explains the data equally well. As a consequence, the data no longer unequivocally support the previous explanation, and the increased loss of pMHC complexes on APCs at high T cell densities is an equally valid interpretation of this striking data.