Cancer vaccination reprograms regulatory T cells into helper CD4 T cells to promote antitumor CD8 T-cell responses

Evaluation of: Sharma MD, Hou DY, Baban B et al.: Reprogrammed Foxp3(+) regulatory T cells provide essential help to support cross-presentation and CD8(+) T cell priming in naive mice. Immunity 33, 942-954 (2010). It has been recognized that natural CD4(+) Foxp3(+) Tregs could display a phenotypic and functional plasticity in an inflammatory microenvironment. Following the loss of key transcription factor, Foxp3 and core inhibitory molecules associated with suppression, Tregs are reprogrammed into proinflammatory effector cells in vivo. However, the biological significance of this conversion is elusive. Sharma et al. demonstrate that in response to vaccines containing antigens, IFA and CpG, a large proportion of Tregs are dedifferentiated into Th1-like effector cells, which coexpress CD40L - a key molecule for CD8 help by licensing dendritic cells. Under certain experimental conditions, these reprogrammed Tregs are absolutely essential in helping the differentiation of CD8 T cells primed by antigen cross-presentation pathways. Treg conversion is diminished by tumor-induced indoleamine 2,3-dioxygenase in tumor-bearing mice, and blockade of indoleamine 2,3-dioxygenase activity in vivo is able to rescue Treg reprogramming. Collectively, in response to signaling from innate immune cells, Tregs are rapidly reprogrammed into Th1-like effector cells, which are also capable of providing timely help for antigen-specific CD8 T cells in the early phase of activation, when the traditional cognate help from conventional CD4 T cells has not yet became available.