Automatic generation of lymphocyte heterogeneity: Division-dependent changes in the expression of CD27, CCR7 and CD45 by activated human naive CD4+ T cells are independently regulated.

Lymphocyte differentiation is a complex process regulated by the integration of signals received through a variety of cell surface receptors that results in populations of differentiated cells that have acquired novel characteristics and effector functions. Differentiation of T and B lymphocytes into effector cells, such as cytokine-secreting CD4+ T cells, cytotoxic CD8+ T cells and Ig-secreting B cells, as well as alterations in cell surface phenotype, have been reported to be associated with cell division. Nevertheless, the genesis of heterogeneity in effector cell type is unknown. A strictly deterministic view holds that heterogeneity arises from distinct signalling histories for each functionally or phenotypically different cell type. In contrast, a probabilistic interpretation proposes that internal stochastic regulation of gene expression gives rise to lymphocytes of mixed phenotypes. To help distinguish between these explanations, we examined the expression of CD27, CCR7, CD45RA and CD45RO by human naive CD4+ T cells in the context of the division history of the lymphocyte. Our results show that each marker independently changes with progressive divisions, strongly supporting the proposal that phenotypic heterogeneity in lymphocytes can arise as the result of independent stochastic processes controlling the expression of individual molecules.