CD4+CD25+ Regulatory T Cells in Viral Infections

CD4+CD25+Tregulatory (Treg) cells are a thymus-derived distinct lineage of T cells that recognize and suppress the expansion and function of potential self-reactive T cell clones, thus maintaining peripheral self-tolerance. It is now established that Treg cells activated in the peripheral immune compartment also modulate immune responses to pathogens. Data suggest that pathogen activated Treg cells in lymph nodes (LN) down-regulate T and B cells responding to the same pathogen, thus minimizing the immunopathology associated with primary immune responses. While Treg cells normally return to a resting state after elimination of the pathogen, in those infections that are not resolved by an anti-viral immune response, they remain chronically activated and immunosuppressive, thereby contributing to a persistent viremia. It is well-established that chronic Hepatitis B and C infections, as opposed to resolved infections, are associated with an increased number or increased activation state of Treg cells that suppress anti-viral CD4+ and CD8+ T cells and contribute to the long-term viremia. In murine models of HSV-1 infection, in vivo depletion of CD25+ Treg cells in mice results in enhanced anti-HSV CD8+ immune responses and more rapid clearance of virus. Similarly, the CD4+ and CD8+ immune deficiency observed in chronic AIDS lentivirus infections have been attributed to immunosuppressive Treg cells capable of suppressing virus-specific CD4+ and CD8+ cytokine and proliferation responses. Whether these activated Treg cells contribute to the host’s failure to eliminate these lentiviruses is not known. However, it has been demonstrated that virus-specific Tcells are anergic, cannot produce IL2, and cannot expand in response to virus peptide stimulation. Activated CD4+CD25+ Treg cells mediate T cell immunosuppression by contact-dependent mechanisms that transduce a signal for transcriptional down-regulation of cytokine genes, including IL2, and induction of T cell anergy. Recent data suggest that Treg-induced T cell anergy is mediated through the TGF-β/TGF-βR signaling pathway. It is clear from the studies described herein that chronic viral infections are characterized by an early and sustained activation of immunosuppressive CD4+CD25+ Treg cells capable of inhibiting anti-viral CD4+ and CD8+ immune responses, which allows for the establishment of long-term infection.