Natural Regulatory T Cells and Persistent Viral Infection

Suppressor T cell is an old term, originally found in the 1970s literature (49, 50), but it was short-lived because advances in molecular biology soon afterward proved that the gene locus, thought to be associated with suppression, was nonexistent. Our recent understanding started with the finding that a small proportion of CD4+ T cells in mice constitutively expressed the high-affinity interleukin-2 (IL-2) receptor α-chain, CD25, and depletion of these cells (now designated natural regulatory T cells Treg) caused autoimmune disease and enhanced responses to foreign antigens (112). This study resulted in a rebound of intense interest in suppressor T cells, and similar cells in humans were identified shortly afterward (78, 98; reviewed in reference 9). It is now well established that natural Treg suppress a diverse range of immune responses in a contact-dependent manner in vitro and in vivo, in response to T-cell receptor (TCR)-mediated stimulation (reviewed in references 43 and 136). Human Treg are less well defined than their murine counterparts and less well studied in general, although the two have features in common. Differences between human and murine Treg, which may complicate the interpretation of human data, have been noted. For instance, in naive inbred pathogen-free mice, natural Treg can be reliably isolated based on their CD25 expression; however, this population in adult outbred humans is inevitably a mixture of Treg and recently activated T effector cells, with the latter expected particularly during an ongoing infection. Opinions are divided over whether Treg play a pathogenic role in chronic viral infection in humans, especially in infections for which the development of a vaccine has so far failed, such as in the case of human immunodeficiency virus (HIV) and hepatitis C virus (HCV). This review considers the key findings in Treg biology and discusses the current position for Treg in viral infection, with particular emphasis on the key aspects of persistent viral infections in humans. Other types of suppressor cells, Tr1 and Th3, that suppress via soluble factors independent of cell-to-cell contact have been reviewed recently (106, 107).