Immunology Cellular Plasticity

John F. Foley

Science Signaling, AAAS, Washington, DC 20005, USA

The differentiation pathway followed by naïve CD4⁺ T cells upon stimulation by antigen-presenting cells depends on the cytokine milieu. Naïve CD4⁺ T cells activated in the presence of interleukin-12 (IL-12) or interferon- (IFN-) differentiate into T helper 1 (T_H1) cells, in a manner dependent on the transcription factor T-bet, whereas cells activated in the presence of IL-4 adopt a T_H2 phenotype, which is dependent on the transcription factor GATA-3. These pathways are thought to be mutually exclusive, and T_H1 and T_H2 lineages are very stable in vivo (see commentary by Zhu and Paul). Furthermore, incubation of stably differentiated T_H2 cells with T_H1-inducing cytokines in vitro does not change their phenotype. Hegazy et al. generated mouse T_H2 cells in vitro from naïve CD4⁺ T cells that had a T cell receptor (TCR) specific for an antigen from lymphocytic choriomeningitis virus (LCMV). The T_H2 cells were transferred into normal mice, which were infected with LCMV 30 days later. Within a week of infection, the majority of the transferred T_H2 cells started to produce the T_H1-type cytokine IFN-, and a subset also produced IL-4, the signature cytokine of T_H2 cells. LCMV-induced production of IFN- in these "T_H1+2" cells depended on the increased abundance of T-bet, while the cells continued to produce GATA-3. In addition to activation of the TCR, induction of T_H1+2 cells in LCMV-infected mice depended on IL-12, IFN-, and the type I IFNs. These cells had a stable phenotype and persisted long after infection. In addition to establishing the plasticity of T_H2 cells, this study also demonstrates the production of T cells with mixed phenotypes, which may lend flexibility to immune responses to viruses.

A. N. Hegazy, M. Peine, C. Helmstetter, I. Panse, A. Frohlich, A. Bergthaler, L. Flatz, D. D. Pinschewer, A. Radbruch, M. Lohning, Interferons direct Th2 cell reprogramming to generate a stable GATA-3⁺T-bet⁺ cell subset with combined Th2 and Th1 cell functions. Immunity 32, 116–128 (2010). [PubMed]

J. Zhu, W. E. Paul, CD4⁺ T cell plasticity: Th2 cells join the crowd. Immunity 32, 11–13 (2010). [Online Journal]