Declines in immune function are well described in the elderly and are considered to contribute significantly to the disease burden in this population. Regulatory T cells (Tregs), a CD4+ T cell subset usually characterized by high CD25 expression, control the intensity of immune responses both in rodents and humans. However, because CD25 expression does not define all Tregs, especially in aged hosts, we characterized Tregs by the expression of FOXP3, a transcription factor crucial for Treg differentiation and function. The proportion of FOXP3+CD4+ Tregs increased in the blood of the elderly and the lymphoid tissues of aged mice. The expression of functional markers, such as CTLA-4 and GITR, was either preserved or increased on FOXP3+ Tregs from aged hosts, depending on the tissue analyzed. In vitro depletion of peripheral Tregs from elderly humans improves effector T cell responses in most subjects. Importantly, Tregs from old FoxP3-GFP knock-in mice were suppressive, exhibiting a higher level of suppression per cell than young Tregs. The increased proportion of Tregs in aged mice was associated with the spontaneous reactivation of chronic Leishmania major infection in old mice, likely because old Tregs efficiently suppressed the production of IFN-γ by effector T cells. Finally, in vivo depletion of Tregs in old mice attenuated disease severity. Accumulation of functional Tregs in aged hosts could therefore play an important role in the frequent reactivation of chronic infections that occurs in aging. Manipulation of Treg numbers and/or activity may be envisioned to enhance the control of infectious diseases in this fragile population.

Endogenous regulatory T cells (Treg) play a central role in the control of excessive or misdirected immune responses against self or foreign Ags. To date, virtually no data are available on the nature of the molecules and signals involved in the trafficking and retention of Treg in tissues where regulation is required. Here, we show that expression of αEβ7 integrin is necessary for the homing of Treg at site of Leishmania major infection. The vast majority of Treg present in the dermis at steady-state conditions or during L. major infection express the αE chain (CD103) of αEβ7. Genetically susceptible BALB/c mice that lack CD103 become resistant to infection, a phenotype that is associated with a poor capacity of Treg to be retained in the infected site. Such susceptible phenotype can be restored when Treg from wild-type mice were transferred in CD103−/− mice. The central role of CD103 in Treg retention was further demonstrated by usage of blocking Abs against CD103 and the transfer of Treg purified from CD103−/− mice. Our results strongly suggest that this molecule is induced and maintained on Treg following or just prior to their arrival in tissues. Furthermore, the expression of CD103 and the subsequent retention of Treg in tissues is highly regulated by their exposure to Leishmania Ag and the level of activation of the APCs they encounter. Thus, CD103, by controlling Treg retention, can contribute to the outcome of chronic infection by Leishmania.

Natural regulatory T (T reg) cells are involved in control of the immune response, including response to pathogens. Previous work has demonstrated that the repertoire of natural T reg cells may be biased toward self-antigen recognition. Whether they also recognize foreign antigens and how this recognition contributes to their function remain unknown. Our studies addressed the antigenic specificity of natural T reg cells that accumulate at sites of chronic infection with Leishmania major in mice. Our results support the idea that natural T reg cells are able to respond specifically to foreign antigens in that they strongly proliferate in response to Leishmania-infected dendritic cells, they maintain Foxp3 expression, and Leishmania-specific T reg cell lines can be generated from infected mice. Surprisingly, the majority of natural T reg cells at the infected site are Leishmania specific. Further, we showed that parasite-specific natural T reg cells are restricted to sites of infection and that their survival is strictly dependent on parasite persistence.