Initial T cell frequency dictates memory CD8+ T cell lineage commitment.

Based on homing characteristics and effector functions, at least two types of memory T cells have been described in CD4+ and CD8+ T cell populations. The original descriptions of central and effector memory T cells suggested that central memory T cells (TCM cells) reside in lymphoid organs and express CCR7 and CD62L, whereas effector memory T cells (TEM cells) reside mainly in nonlymphoid tissues, do not express CCR7 or CD62L and have immediate effector functions1–3. This raised the question of how TCM cells and TEM cells are generated and whether each is the product of interdependent or separate lineages. Three models of differentiation have been proposed, with the first being that TCM cells provide a continual source of TEM cells. This model is based on the findings that memory CCR7+ T cells in short-term in vitro culture can lose expression of this chemokine receptor and in the process become functionally competent1,4. Analysis of the T cell receptor (TCR) repertoire of human blood memory CD8+ T cells has suggested an additional possibility in which TCM and TEM cells represent mostly separate lineages5. In contrast, an alternative model has indicated that over time TEM cells convert to TCM cells6. This conclusion was derived from analysis of TCR-transgenic CD8+ memory T cells specific for lymphocytic choriomeningitis virus (LCMV) glycoprotein 33 (gp33) that had been separated by virtue of CD62L expression. In this system, adoptively transferred CD62L− memory T cells convert to CD62L+ memory cells, however, the reverse does not occur. This discordance between models of memory CD8+ T cell lineage development may be due in part to differences in experimental systems or could reflect a fundamental difference between human and mouse CD8+ memory T cells. To address those discrepancies, we have compared here the generation of memory cell lineages in adoptively transferred TCR-transgenic CD8+ T cells versus endogenous CD8+ T cells responding to the same infection in vivo. Our results indicated that commitment to a particular memory cell lineage was governed by the initial naive T cell precursor frequency. Moreover, the differentiative and proliferative capacity of memory cell subsets was dependent on the amount of initial clonal competition.