A Single Peripheral CD8+ T Cell Can Give Rise to Progeny Expressing Type 1 And/or Type 2 Cytokine Genes and Can Retain Its Multipotentiality Through Many Cell Divisions

The lineage relationships between murine CD8(+) T cells with different cytokine profiles were investigated by paired-daughter analysis in the presence and absence of the type 2 cytokine-inducing stimulus, interleukin 4 (IL-4). Single CD8(+) CD44(low) lymph node T cells were activated to divide at high frequency with IL-2 and immobilized antibodies to CD3, CD8, and LFA-1. When these parent cells were subcloned by transferring their daughter or granddaughter cells into secondary cultures with or without IL-4, the subclones expressed diverse combinations of the mRNAs for the type 1 cytokines, interferon gamma (IFN-gamma), and IL-2, and the type 2 cytokines, IL-4, IL-5, IL-6, and IL-10. Frequencies of subclones that expressed IL-4, IL-6, and, to a lesser extent, IL-2, IL-5, and IL-10 were higher among those grown with IL-4, but a significant proportion of those grown without exogenous IL-4 also expressed one or more type 2 cytokines. Subclones within 89% of families displayed different cytokine profiles, indicating that their parent cells were multipotential for this function. Because 98% of parent cells yielded subclones that produced type 1 cytokines and 77% yielded type 2 cytokine producers, we conclude that type 1 and type 2 cytokine-producing CD8(+) T cells can be derived from a common precursor. Similar analyses performed by subcloning after >/=7 or >/=13 cell divisions without IL-4 showed that many CD8(+) T cells retained the potential to shift toward a type 2 cytokine profile in response to IL-4, even after prolonged expansion under conditions that favored type 1 cytokine expression. CD8(+) T cells that express type 1 and/or type 2 cytokines therefore are derived from the same peripheral T cell lineage whose multipotentiality can persist through many cell divisions.