Heterogeneity of single cell cytokine gene expression in clonal T cell populations.

Abstract

SunM~aryT helper type 0 (Th0), Thl, and Th2 CD4 + T cell cloues derived from a T cell receptor cx/fl (TCR-alfl) transgenic mouse were activated by antigen presented on "artificial" antigen-presenting cells that expressed or lacked the costimulatory molecule B7-1, and were analyzed for single cell eytokine mRNA expression by in situ hybridization. There was significant heterogeneity in the frequency of T cells that expressed individual cytokine mRNAs within each donal population, suggesting that transcriptional control of each of the cytokine genes was not coordinate within an individual cell. The majority of antigen-stimulated Thl cells expressed mRNA for interferon "y (IFN-7), but far fewer cells in the same population expressed interleukin 2 (IL-2). Similarly, the frequency of IL-4-expressing cells was greater than that of IL-5-or IL-10-expressing cells in the same Th2 population, but the difference in expression frequencies was more variable between dones. The expression frequencies of each of the cytokines was quite heterogeneous in the antigenactivated Th0 population. The principal effect of increased antigen on the activation of individual cytokine genes in each of the clonal populations was to increase recruitment of mRNA-positive cells, with little or no effect on the level of cytokine mRNA expression in individual positive cells. The effects of B7 costimulation were variable depending on the cytokiue gene analyzed. B7 costimulation markedly increased the frequency and the level of IL-2 mRNA expression in individual positive cells in the Thl and Th0 populations, with less effect on the recruitment and single cell expression level of IFN-% IL-4 frequencies were modestly increased by B7 costimulation of the Th2 clones, but there was no detectable increase in single cell IL-4 expression level. The observed patterns of cytokine mRNA expression favor a model of T cell activation in which all-or-none, rather than graded, responses of cytokine genes are dominant.

Shift toward T lymphocytes with a T helper 1 cytokine‐secretion profile in the joints of patients with rheumatoid arthritis

“…These findings are conistent with those of a previous study (24) that suggested I model of T cell activation in which, at a single-cell evel, all-or-none rather than graded responses of cytoLine genes were dominant. Our data extrapolate from he results obtained in murine models to human disease.…”

Secretion of IL-2 and IFN-γ, But Not IL-4, by Antigen-Specific T Cells Requires Extracellular ATP

“…However, it was theoretically possible that the differential requirement for E-NTPDase activity might be attributed to differences in TCR specificity or avidity between clones that fortuitously associated with Th1 or Th2 cells in the above experiments. To address this possibility, the effect of 5Ј-FSBA was tested on T cell clones derived from transgenic mice expressing the OVA 323-339 -specific TCR from DO11.10 T cells (30). As previously reported, the DO11.10 Th1 cells produced IFN-␥ but no detectable IL-4; Th2 cells produced IL-4, IL-5, and IL-10; and Th0 cells produced cytokines characteristic of both Th1 and Th2, including IFN-␥, IL-4, IL-5, and IL-10, upon stimulation with Ag and APCs (19,20).…”

T Cell Effector Function and Anergy Avoidance Are Quantitatively Linked to Cell Division

“…While individual primary T cells exhibit a relatively uniform pattern of early signal transduction and activation in response to optimal TCR and costimulatory receptor ligation (1,2), a large degree of heterogeneity can be observed with respect to functional behavior such as cytokine production (3)(4)(5)(6)(7). A similar degree of diversity characterizes the proliferative behavior of individual activated T cells.…”