Immunosuppressive CD4+CD25+FoxP3+ regulatory T (Treg) cells, which play a pivotal role in peripheral tolerance , have also been found to play a role in the immunopathogenesis of disease caused by certain persistent infections [2,3]. The overall impact of Treg cells on HIV/simian immunodeficiency virus (SIV) disease progression remains controversial and has proven difficult to assess due to lack of specific inhibitors of Treg-cell activity and the complex role of immune activation in HIV/SIV disease. Treg cells potentially exert contrasting effects: slowing progression by suppressing generalized immune hyperactivation and HIV replication in non-Treg cells, or accelerating progression by suppressing virus-specific immune responses, and/or contributing to the loss of T helper-17 cells, thereby increasing immune activation mediated by microbial translocation from the gut [3–7]. Although there is conflicting data regarding the frequency of Treg cells in the blood during the course of infection, it is largely agreed upon that Treg-cell frequencies are elevated in gut-associated, and to some extent, peripheral, lymphoid tissue in untreated SIV and HIV infection [8–11]. The mechanism(s) whereby Treg cells might accumulate in lymphoid tissue include the following: migration of Treg cells out of the blood into tissue sites of viral replication and immune activation [8,12]; reduced susceptibility of CD4+ Treg cells, compared with other CD4+ T-cell subsets, to infection-associated death ; or the generation of adaptive or induced (i) Treg cells at lymphoid tissue sites [14–16].
In this issue of AIDS, Presicce et al. make important observations supporting the latter hypothesis. Their study demonstrates that myeloid dendritic cells (mDCs) of SIV-positive animals are inherently more effective in generating iTreg cells than those of uninfected animals. Both immature and mature mDCs isolated from the spleen and mesenteric lymph nodes (MLNs) of SIV-positive, but not SIV-negative, animals effectively generated a proliferating CD25+FoxP3+ CD4+ T-cell population when cultured with autologous CD25− CD4+ T cells in the absence of exogenous stimuli. Mature mDCs (CD83+), which were more effective than immature mDCs for this effect, were found at higher frequencies in the MLNs of infected animals, and these frequencies correlated with viral load and duration of infection. Overall, these data suggest that chronic SIV, and presumably HIV, infection generates a microenvironment in the lymphoid tissue that conditions dendritic cells and/or CD4+ T cells to generate and expand iTreg cells.
Under homeostatic conditions in the gut-associated lymphoid tissue and MLN, CD103+ dendritic cells preferentially generate FoxP3+ Treg cell populations that play an important role in maintaining immune tolerance and determining the balance of regulatory and effector T cells at those sites . Although Presicce et al. found that CD103 expression did not appear to influence conversion of T cells to iTreg cells, this conclusion should be viewed with caution because these analyses may have been compromised by the limited amount of data. Under inflammatory conditions, as generated by certain chronic infections, increased expression of immunosuppressive or anti-inflammatory factors, such as indoleamine 2, 3-dioxygenase (IDO) and transforming growth factor-β, can modify the interaction between several dendritic cell subsets and naive CD4+ T cells, so that iTreg, instead of effector, cells are generated . A number of factors that condition dendritic cells and/or T cells to promote iTreg-cell generation and expansion have been reported to be elevated in tissue during SIV/HIV infection [3,8,10,12,14,15,19]. What the study by Presicce et al. accomplishes is to link these observational studies to the actual generation of iTreg cells by autologous lymphoid tissue mDCs. Plasmacytoid dendritic cells (pDCs) were not examined by Presicce et al. because cell numbers were insufficient to do this. Manches et al. have shown that pDCs stimulated with HIV in vitro are capable of inducing Treg cells through an IDO-dependent mechanism. However, pDCs recruited to the colon and rectum during the first several months of SIV infection were found to produce little IDO and to contribute to immune activation rather than suppression .
Clearly, future studies are needed to delineate which dendritic cell subsets and pathways are involved in the generation of iTreg cells in the context of SIV/HIV infection. Importantly, the extent of iTreg-cell generation and the means by which this occurs may vary depending on the tissue site and the duration of infection. Whether Treg-cell conversion can, or should be, a target for therapeutic intervention remains an open question.
Conflicts of interest
There are no conflicts of interest.
1. Sakaguchi S, Ono M, Setoguchi R, Yagi H, Hori S, Fehervari Z, et al. Foxp3+ CD25+ CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease
2. Belkaid Y, Rouse BT. Natural regulatory T cells in infectious disease
. Nat Immunol
3. Nixon DF, Aandahl EM, Michaëlsson J. CD4+CD25+ regulatory T cells in HIV infection
. Microbes Infect
4. Eggena MP, Barugahare B, Jones N, Okello M, Mutalya S, Kityo C, et al. Depletion of regulatory T cells in HIV infection is associated with immune activation
. J Immunol
5. Moreno-Fernandez ME, Rueda CM, Rusie LK, Chougnet CA. Regulatory T cells control HIV replication in activated T cells through a cAMP-dependent mechanism.Blood
6. Kinter AL, Horak R, Sion M, Riggin L, McNally J, Lin Y, et al. CD25+ regulatory T cells isolated from HIV-infected individuals suppress the cytolytic and nonlytic antiviral activity of HIV-specific CD8+ T cells in vitro
. AIDS Res Hum Retroviruses
7. Kanwar B, Favre D, McCune JM. Th17 and regulatory T cells: implications for AIDS pathogenesis
. Curr Opin HIV AIDS
8. Andersson J, Boasso A, Nilsson J, Zhang R, Shire NJ, Lindback S, et al. The prevalence of regulatory T cells in lymphoid tissue is correlated with viral load in HIV-infected patients
. J Immunol
9. Epple HJ, Loddenkemper C, Kunkel D, Troger H, Maul J, Moos V, et al.Mucosal but not peripheral FOXP3+ regulatory T cells are highly increased in untreated HIV infection and normalize after suppressive HAART.Blood
10. Boasso A, Vaccari M, Hryniewicz A, Fuchs D, Nacsa J, Cecchinato V, et al. Regulatory T-cell markers, indoleamine 2,3-dioxygenase, and virus levels in spleen and gut during progressive simian immunodeficiency virus infection
. J Virol
11. Shaw JM, Hunt PW, Critchfield JW, McConnell DH, Garcia JC, Pollard RB, et al. Increased frequency of regulatory T-cells accompanies increased T-cell immune activation in rectal mucosa of HIV+ non-controllers
. J Virol
12. Ji J, Cloyd MW. HIV-1 binding to CD4 on CD4+CD25+ regulatory T cells enhances their suppressive function and induces them to home to, and accumulate in, peripheral and mucosal lymphoid tissues: an additional mechanism of immunosuppression
. Int Immunol
13. Allers K, Loddenkemper C, Hofmann J, Unbehaun A, Kunkel D, Moos V, et al. Gut mucosal FOXP3+ regulatory CD4+ T cells and nonregulatory CD4+ T cells are differentially affected by simian immunodeficiency virus infection in rhesus macaques
. J Virol
14. Krathwohl MD, Schacker TW, Anderson JL. Abnormal presence of semimature dendritic cells that induce regulatory T cells in HIV-infected subjects
. J Infect Dis
15. Estes JD, Li Q, Reynolds MR, Wietgrefe S, Duan L, Schacker T, et al. Premature induction of an immunosuppressive regulatory T cell response during acute simian immunodeficiency virus infection
. J Infect Dis
16. Belkaid Y, Oldenhove G. Tuning microenvironments: induction of regulatory T cells by dendritic cells
17. Presicce P, Shaw JM, Miller CJ, Shacklett BL, Chougnet CA. Myeloid dendritic cells isolated from tissues of SIV-infected rhesus macaques promote the induction of regulatory T cells.AIDS
18. Matteoli G, Mazzini E, Iliev ID, Mileti E, Fallarino F, Puccetti P, et al. Gut CD103+ dendritic cells express indoleamine 2,3-dioxygenase which influences T regulatory/T effector cell balance and oral tolerance induction
19. Manches O, Munn D, Fallahi A, Lifson J, Chaperot L, Plumas J, et al. HIV-activated human plasmacytoid DCs induce Tregs through an indoleamine 2,3-dioxygenase-dependent mechanism
. J Clin Invest
20. Kwa S, Kannanganat S, Nigam P, Siddiqui M, Shetty RD, Armstrong W, et al. Plasmacytoid dendritic cells are recruited to the colorectum and contribute to immune activation during pathogenic SIV infection in rhesus macaques