Evidence for the stochastic acquisition of cytokine profile by CD4+ T cells activated in a T helper type 2‐like response in vivo

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Abstract
The diversity of cytokine production patterns displayed by T cells activated in vivo was investigated by analyzing short‐term antigen‐specific CD4+ T cell clones and single CD4+ T cells derived from draining lymph nodes of mice undergoing a T helper 2 (Th2)‐like response to keyhole limpet hemocyanin (KLH). On average, 2.7% of CD4+ lymph node cells gave rise to clones in the presence of the immunizing antigen and, of these, about 90% secreted interleukin‐4 (IL‐4) and 20% secreted interferon‐γ (IFN‐γ) when restimulated after 2 weeks in vitro. Almost all IFN‐γ‐producing clones co‐produced IL‐4. The definition of clones as positive or negative for cytokine synthesis depended on assay sensitivity, however, since their titers were distributed continuously from the threshold of detection over at least a 1000‐fold range. Reverse‐transcription polymerase chain reaction analysis of 59 clones revealed multiple patterns of co‐expression of IL‐2, IL‐3, IL‐4, IL‐6, IFN‐γ and granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) mRNA. Although most clones contained detectable IL‐4 and IL‐6 mRNA and a minority contained IFN‐γ mRNA, only 1 clone expressed the canonical Th2 cytokine profile. The observed frequencies of mRNA co‐expression for most of the six cytokines (including IL‐4 with IFN‐γ), and the frequency of co‐secretion of IL‐4 and IFN‐γ, were not significantly different from those predicted for random association. Independent regulation of IL‐4 and IFN‐γ mRNA expression was confirmed at the single‐cell level in a polyclonal population of KLH‐primed CD4+ cells, among which co‐expression of these cytokines again occurred at the frequency predicted for a random event. The data suggest that the polarization of this immune response towards a Th2 cytokine profile is achieved by altering the probabilities of expression of the IL‐4, IFN‐γ and other cytokine genes at the population level, rather than by selective expansion of a distinct T cell subset.

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