As the immune system develops, T cells are selected or regulated to become tolerant of self antigens and reactive against foreign antigens. In mice, the induction of such tolerance is thought to be attributable to the deletion of self-reactive cells. Here, we show that the human fetal immune system takes advantage of an additional mechanism: the generation of regulatory T cells (T _regs ) that suppress fetal immune responses. We find that substantial numbers of maternal cells cross the placenta to reside in fetal lymph nodes, inducing the development of CD4+CD25 ^high FoxP3+ T _regs that suppress fetal antimaternal immunity and persist at least until early adulthood. These findings reveal a form of antigen-specific tolerance in humans, induced in utero and probably active in regulating immune responses after birth.

Gut-resident microbial populations may influence intestinal homeostasis during HIV disease.

The pathogenesis of human and simian immunodeficiency viruses is characterized by CD4⁺ T cell depletion and chronic T cell activation, leading ultimately to AIDS. CD4⁺ T helper (T_H) cells provide protective immunity and immune regulation through different immune cell functional subsets, including T_H1, T_H2, T regulatory (T_reg), and interleukin-17 (IL-17)–secreting T_H17 cells. Because IL-17 can enhance host defenses against microbial agents, thus maintaining the integrity of the mucosal barrier, loss of T_H17 cells may foster microbial translocation and sustained inflammation. Here, we study HIV-seropositive subjects and find that progressive disease is associated with the loss of T_H17 cells and a reciprocal increase in the fraction of the immunosuppressive T_reg cells both in peripheral blood and in rectosigmoid biopsies. The loss of T_H17/T_reg balance is associated with induction of indoleamine 2,3-dioxygenase 1 (IDO1) by myeloid antigen-presenting dendritic cells and with increased plasma concentration of microbial products. In vitro, the loss of T_H17/T_reg balance is mediated directly by the proximal tryptophan catabolite from IDO metabolism, 3-hydroxyanthranilic acid. We postulate that induction of IDO may represent a critical initiating event that results in inversion of the T_H17/T_reg balance and in the consequent maintenance of a chronic inflammatory state in progressive HIV disease.

Lymphocytes Layer It On: Cells of the immune system begin to develop from hematopoietic stem cells (HSCs) during fetal life. In the adult, HSCs continue to produce immune cells to replenish dying cells or in response to an infection. In mice and birds, immune cell development occurs in a “layered” manner, whereby distinct populations of HSCs that arise at different times during development generate distinct immune cell lineages. In contrast, development of human immune cells, and T lymphocytes in particular, is thought to be linear. Mold et al. (p. 1695 ; see the Perspective by Betz ) now show that T lymphocyte development in humans is also “layered,” and strategically so. T cells that arise from fetal HSCs are enriched in regulatory T cells, which promote immune tolerance, rather than classical T cells, which readily respond to foreign antigen. By favoring the development of regulatory T cell populations during fetal life, the immune system is perhaps better able to keep responses to maternal antigens in check. The development of large numbers of classical T cells is delayed until after birth when infectious agents represent a more imminent threat.

Chronic immune activation and progression to AIDS are observed after SIV infection in macaques but not in natural host primate species. To better understand this dichotomy, we compared acute pathogenic SIV infection in pigtailed macaques (PTs) to non-pathogenic infection in African green monkeys (AGMs). SIVagm-infected PTs, but not SIVagm-infected AGMs, rapidly developed systemic immune activation, marked and selective depletion of IL-17-secreting (Th17) cells, and loss of the balance between Th17 and T regulatory (Treg) cells in blood, lymphoid organs, and mucosal tissue. The loss of Th17 cells was found to be predictive of systemic and sustained T cell activation. Collectively, these data indicate that loss of the Th17 to Treg balance is related to SIV disease progression. Natural infection by the simian immunodeficiency virus (SIV) in over 40 different species of African non-human primates is not accompanied by progression to acquired immunodeficiency syndrome (AIDS). To understand this phenomenon, we have performed a detailed virologic, immunologic, and gene expression analysis of acute SIV infection of two disparate species: the African green monkey (AGM), in which SIV infection is nonpathogenic, and the Asian pigtailed macaque (PT), in which SIV infection results in AIDS. After experimental infection, animals of both species developed high viral loads. In the PTs, viremia was associated with CD4⁺ T cell depletion in the peripheral blood and multiple signs of persistent immune activation and inflammation. Such pathology was not observed in AGMs. Notably, the AGMs maintained high and balanced levels of two subset populations of CD4⁺ T cells, e.g., the immunosuppressive T regulatory (Treg) and the IL-17 producing (Th17) populations, whereas the PTs did not. Further analysis of the role of Th17 and Treg balance during pathogenic lentiviral infection may provide novel insights into our understanding of SIV and HIV pathogenesis and future thoughts about vaccine development.

Introduction: Plasmacytoid dendritic cells (pDCs) constitutively express two members of the Toll-like receptor (TLR) family, TLR-9 and TLR-7, through which they can be stimulated to produce high levels of interferon (IFN)-α, a key mediator of the pathogenesis of systemic lupus erythematosus (SLE). Given the known efficacy of hydroxychloroquine (HCQ) in the treatment of SLE, we examined its ability to inhibit such pDC function in vivo. Methods: Peripheral blood mononuclear cells (PBMCs) from SLE subjects treated or not with HCQ and from healthy controls were stimulated with the TLR-9 agonist, CpG oligodeoxynucleotides (CpG-A ODN)-2216, and the TLR-7 agonist, imiquimod. The proportion of monocytes, B cells, myeloid dendritic cells, pDCs, and natural killer (NK) cells producing IFN-α and tumor necrosis factor alpha (TNF-α) was then analyzed by multiparameter flow cytometry. Results: After TLR-9/7 stimulation in both SLE and healthy subjects, significant production of IFN-α and TNF-α was only observed in pDCs. TLR-7 and TLR-9 induced IFN-α and TNF-α production by pDCs from subjects with SLE was decreased relative to that found in controls (TLR-9/IFN-α, P < 0.0001; TLR-9/TNF-α P < 0.0001; TLR-7/TNF-α P = 0.01). TLR-9 and TLR-7 induced IFN-α and TNF-α production by pDCs was severely impaired in 36% (TLR-9) and 33% (TLR-7) of SLE subjects. In almost all cases, these subjects were being treated with HCQ (HCQ vs. no HCQ: impaired TLR-9/IFN-α, P = 0.0003; impaired TLR-7/IFN-α, P = 0.07; impaired TLR-9/TNF-α, P < 0.009; impaired TLR-7/TNF-α, P < 0.01). Conclusions: Treatment with HCQ is associated with impaired ability of pDCs from subjects with SLE to produce IFN-α and TNF-α upon stimulation with TLR-9 and TLR-7 agonists.