Regulatory T Cells and Viral Disease

The mammalian immune system has the ability to distinguish self from non-self-antigens, a phenomenon which begins in the thymus during T cell development. T cells that express a fully rearranged T cell receptor (TCR) with a high affinity for self-antigens presented in the thymus are deleted or undergo anergy in a process known as negative selection. Because of this mechanism, T cells in the periphery are primarily specific for non-self-antigens. However, this process is somewhat inefficient, because some self-reactive cells escape deletion therefore additional mechanisms are required to maintain peripheral immune tolerance. Regulatory T cells (Tregs) are a distinct subset of T cells that are critical for maintaining both immune homeostasis and peripheral immune tolerance. Tregs are typically identified by expression of the forkhead box 3 (FoxP3) transcription factor. The majority of FoxP3+ cells also express CD4 and express high levels of the IL-2 receptor (CD25). Additional subsets of Tregs that have been described in humans and mice include Tr1 cells, T helper 3 cells (Th3), NK cells, and CD8+ Tregs (Beissert S, 2006). CD4+ T cells that express high levels the IL-2 receptor (CD25high) do not respond to T cell receptor (TCR) activation or mitogen stimulation, and inhibit IL-2 transcription in CD25cells. Suppression of CD25cells is contact dependent, and requires activation of the Tregs through the TCR; however, once activated, the suppressor effector function is nonspecific (Thornton AM, 2000). In mice and humans, FoxP3+ cells also express high levels of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and glucocorticoid-induced tumor necrosis factor receptor (GITR) on the surface (Bacchetta R, 2005). CD4+CD25+ T cells suppress the immune response to some viruses, protozoa, and bacteria, and aid in the survival of intracellular pathogens (Sakaguchi, 2003) most likely by potent suppression of proliferation and IFN- production of both CD4+ and CD8+ T lymphocytes (Bacchetta R, 2005). Tr1 cells secrete high amounts of IL-10 and moderate amounts of TGF-. Inhibiting IL-10 with neutralizing antibody blocks the suppressor effects of Tr1 cells (Beissert S, 2006). Th3 cells produce high concentrations of TGF- and moderate amounts of IL-10, and the suppressor effects are not antigen specific (Beissert S, 2006). Interestingly, Th3 cells suppress the activation of both Th1 and Th2 cell clones while other subsets primarily inhibit Th1 cells and have no effect on Th2 cells (Beissert S, 2006). A number of studies have shown that Tregs affect the magnitude of immunity and outcome of viral infections, especially with persistent viruses that give rise to chronic lesions (Rouse BT, 2006). Depletion of Tregs prior to infection using a monoclonal antibody against the IL-2 receptor results in enhanced in vivo CD8+ and CD4+ T lymphocyte proliferation, and increased mucosal antibody levels in response to herpes