Treg migrate to the grafted tissue. Activated Treg convert ATP released by inflamed tissues to adenosine via the ectoenzymes CD39 and CD73. Local adenosine could contribute to the initial “privileged” microenvironment. Treg also secrete TGF-β and IL-10 which inhibit the maturation and migration of dendritic cells (DC). These “decommissioned” DC can secrete catabolic enzymes for depletion of essential amino acids (EAA) and, therefore, induce apoptosis of effector T cells. Moreover, the “privileged” tissues could release pro-apoptotic galectin-9 which binds to TIM-3 expressed by effector T cells such as Th1 and Th17. This further amplifies the immunosuppressive microenvironment. Each of these components within the graft can further reinforce the local anti-inflammatory state such that any naive T cell, migrating into this area, will be converted to induced Treg (iTreg) through<unk> . The iTreg then expand and further suppress immunity in the “privileged” microenvironment. During a tolerant state potential effector cells remain but are tightly regulated by induced antigen-specific CD4+ regulatory T cells (iTregs). Many subsets of iTregs play a part in this proces, but CD4+CD25+FoxP3+ Tregs play a key role, because they have the ability to convert conventional T cells into iTregs directly by secretion of the suppressive cytokines TGF-β, IL-10 or IL-35, or indirectly via dendritic cells (DCs). Production of IL-10 induces the formation of another population of regulatory T cells called Tr1. Tr1 cells are dependent on IL-10 and TGF-β as well as Tregs, but differ from them by lacking expression of Foxp3. High IL-10 production is characteristic for Tr1 cells themselves and they also produce TGF-β. In the presence of IL-10 can be also induced tolerogenic DCs from monocytes, whose production of IL-10 is also important for Tr1 formation. These interactions lead to the production of enzymes such as IDO (indolamine 2,3-dioxygenase) that catabolize essential amino acids. This microenvironment with a lack of essential amino acids together with other signals results in mTOR (mammalian target of rapamycin) inhibition which, particularly in synergy with TGF-β, direct the induction of new FoxP3 (forkhead box protein 3) expressing Tregs.
Infectious tolerance
Immune tolerance
Peripheral tolerance
Intravascular immunity
Vaccine shedding
Alloimmunity
Immunocompetence
Viral pathogenesis