Cytokines Associated with Activation of CD4⁺CD25⁺Foxp3⁺ T Regulatory Cells

The survival and activation of both effector and regulatory CD4⁺T cells are promoted by cytokines in a complex series of interactions. Alloantigen-specific Regulatory T cells (Treg) constitutively express IL-2 receptor (CD25) and Foxp3. This discovery arose as the cells that transfer the alloantigen-specific transplant tolerance die in culture with specific alloantigens, unless the cultures are supplemented with cytokines from activated lymphocytes. One such cytokine was IL-2, but other cytokines are essential. We describe how the activation of Treg by antigens depends on cytokines produced by antigen-activated effector T cells. These cytokines also drive in parallel the activation of Treg. The Treg are induced to express similar transcription factors and chemokine receptors and have a similar cytokine responsiveness to the activated T effector cells. The activation of Treg by antigens is a two-step process: the first requires cytokines produced by effector T cells early in their activation, and the second step is driven by cytokines produced later by effector T cells during activation. Cytokines from Type 1 responses promote the induction of Th1-like Treg. Likewise, cytokines produced in Type 2, Type 3, and Tfh responses induce different pathways of Treg activation. Understanding the pathways for the activation and expansion of potent antigen-specific Treg will help produce Treg to control allograft rejection or autoimmunity. Currently, the complexity of the numerous potential pathways of activation of Treg remains incompletely understood. The dogma that IL-2 is the only driver of Treg activation may have hindered the development of highly potent antigen-specific Treg for therapy.