Natural Regulatory T Cells and Persistent Virus Infection
Suppressor T cell is an old term, originally found in the 1970s literature, 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 alpha-chain, CD25, and depletion of these cells (now designated natural regulatory T cells [Treg]) caused autoimmune disease and enhanced responses to foreign antigens. This study resulted in a rebound of intense interest in suppressor T cells, and similar cells in humans were identified shortly afterward. 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. 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 nave 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.
Treg dysregulation has been reported to be present in many examples of persistent viral infections. It is unclear if the altered Treg function is a cause or effect of viral persistence in the host. However, since the deficiency in Treg number and/or function may cause virus-associated autoimmune tissue destruction and enhanced Treg frequency and activity may suppress antiviral immunity, Treg dysregulation does not appear to be an innocent coincidence of viral persistence. It is hard to predict whether therapeutic manipulation of Treg could help to resolve chronic viral infection or limit its damage. In patients with persistent HCV infection, virus-specific Treg outnumbers virus-specific T effector cells by far, and we wonder if, during the long course of the disease, Treg are somehow expanded while T effector cells are deleted. A central question remaining for HCV, as well as for other viral diseases, is whether Treg require priming to recognize virus antigen, and if so, how this priming would occur. Work with HIV and FV supports the hypothesis that certain viruses can subvert DC function so that a nave T cell is primed to become a Treg rather than an effector T cell, or alternatively, if Treg and T effector cells are distinct lineages, nave Treg may be preferentially primed over T effector cells. In some situations, Treg are deleted as a consequence of virus replication or by unknown mechanisms, adding one more layer of complexity to this already difficult topic. One important practical consideration is whether dominant Treg epitopes exist. Although it is speculated that Treg and T effector cells may recognize the same epitopes, the location and hierarchy of Treg epitopes in any viral protein are largely unknown. Given that vaccine development has so far failed for HIV and HCV, the removal of dominant Treg epitopes, if they exist, may increase the chances of developing successful vaccines.
Natural Regulatory T Cells and Persistent Viral Infection
J Virol 2008 82: 21-30
Tags: Biology, Immunology, Microbiology, Science, Vaccines, Virology
