CD4+ Th2 cells function alike effector Tr1 and Th1 cells through the deletion of a single cytokine IL-6 and IL-10 gene

Depending on polarizing cytokine signals during activation by antigen, naïve CD4+ T cells can be stimulated and differentiated into distinct functional CD4+ T cell subsets such as Th1, Th2 and Tr1 cells. Among them, Th2 cells are pathogenic in allergic diseases such as asthma, which are characterized by transcription factor GATA3 expression and IL-4, IL-5, IL-6, and IL-10 cytokine secretion. The overlapping expression of some signature cytokines by Th2 and other subsets of CD4+ T cells may not only indicate the plasticity of CD4+ T cells, but could also suggest the possibility of the deletion of a single signature cytokine gene leading to the functional differentiation of naïve CD4+ T cells into effector Th1 or Tr1 cells under Th2 differentiation conditions. In this work, we stimulated naïve CD4+ T cells derived from OT II mice or OT II mice that were deficient in individual cytokines (IL-4, IL-5, IL-6 and IL-10) with OVA-pulsed dendritic cells (DCOVA) in the presence of IL-4 and anti-IFN-γ, to generate OVA-specific wild-type (WT) Th2, and Th2(IL-4 KO), or Th2(IL-5 KO), or Th2(IL-6 KO), or Th2(IL-10 KO) cells, and to assess their capacity in modulating DCOVA-induced CD8+ cytotoxic T lymphocyte (CTL) responses, and antitumor immunity in WT C57BL/6 mice. We conclusively demonstrate that GATA-3-expressing Th2 cells enhance DCOVA-induced CTL responses via IL-6 secretion. We also show that IL-6 and IL-10 gene deficient Th2(IL-6 KO) and Th2(IL-10 KO) cells, but not IL-4 and IL-5 gene deficient Th2(IL-4 KO) and Th2(IL-5 KO) cells, behave like functional Tr1 and Th1 cells by inhibiting and enhancing DCOVA-induced OVA-specific CD8+ CTL responses and antitumor immunity, respectively. We further elucidate that inhibition and enhancement of DCOVA-induced OVA-specific CTL responses by Th2(IL-6 KO) and Th2(IL-10 KO) cells are mediated by their immune suppressive IL-10 and pro-inflammatory IL-6 secretion, respectively. Taken together, our study suggests that deletion of a single cytokine gene IL-6 and IL-10 makes CD4+ Th2 cells become effector CD4+ Tr1- and Th1-like cells, respectively. Our data thus not only provide new evidence for another type of CD4+ T cell plasticity, but also have a potential to impact the development of a new direction in immunotherapy of allergic diseases.

► Deletion of a single cytokine gene IL-6 differentiates naive CD4+ T cells into functional CD4+ Tr1 under Th2 differentiation conditions.
► Deletion of a single cytokine gene IL-10 differentiates naive CD4+ T cells into functional CD4+ Th1 under Th2 differentiation conditions.
► Our data provide new evidence for another type of CD4+ T cell plasticity, which may have positive impact on the treatment of allergic diseases.