The cytokine transforming growth factor-beta (TGF-beta) converts naïve T cells into regulatory T (Treg) cells that prevent autoimmunity. However, in the presence of interleukin-6 (IL-6), TGF-beta has also been found to promote the differentiation of naïve T lymphocytes into proinflammatory IL-17 cytokine-producing T helper 17 (T(H)17) cells, which promote autoimmunity and inflammation. This raises the question of how TGF-beta can generate such distinct outcomes. We identified the vitamin A metabolite retinoic acid as a key regulator of TGF-beta-dependent immune responses, capable of inhibiting the IL-6-driven induction of proinflammatory T(H)17 cells and promoting anti-inflammatory Treg cell differentiation. These findings indicate that a common metabolite can regulate the balance between pro- and anti-inflammatory immunity.

IntroductionA progressive reduction in CD4 ϩ T-helper lymphocytes is the main feature of HIV infection and leads to a depression in adaptive immunity. 1 Innate immunity is also important in the host response to HIV infection and can be impaired during the course of this infection. Dendritic cells (DCs) can promote HIV transmission, [2][3][4][5] and DC function 6 and number 7 decline with HIV infection. The effector functions of monocytes and macrophages, including phagocytosis and intracellular oxidative responses, can be found decreased in HIV-infected subjects 8,9 and in cultured cells in the presence of HIV. [10][11][12][13] Superoxide production by neutrophils 14 as well as natural killer cell function as measured by the lymphokineactivated killer activity and responsiveness to interferon-␣ (IFN-␣) 15,16 have been shown to be defective in HIV-infected subjects.An important part of the innate defense against virus is the production of the type I IFNs, IFN-␣, and IFN-␤. 17 IFN-␣/␤ not only directly inhibit HIV replication, 18-20 but also have important adjuvant effects on a variety of immune cell types, such as monocytes, natural killer cells, 21 and T cells. [22][23][24][25][26] The in vitro type I IFN production by total peripheral blood mononuclear cells (PBMCs) was shown to be impaired during the course of HIV infection, and this impairment was associated with the occurrence of opportunistic infections. 27,28 CD4 ϩ CD11c Ϫ lineage marker Ϫ type 2 DC precursors (pre-DC2) were recently shown to be the natural IFN-␣/␤-producing cells in human blood. 29,30 IPCs produce up to 1000 times more IFN-␣ than any other blood cell type in response to viral stimulation. 29 Whether this impairment of IFN-␣/␤ production in HIV-infected individuals is due to a functional defect or to a reduction in number of IPCs is not known.In this study, we show that blood IPCs are severely decreased in AIDS patients but increased in asymptomatic long-term survivors (LTSs). The drop in IPC number and a decrease in their induced IFN production are associated with the presence of opportunistic infections and active Kaposi sarcoma. Our findings bring a new insight into the physiopathology of HIV infection and identify the IPC count as a new parameter to monitor the status of the immune system of HIV-infected subjects. Patients, materials, and methods HIV-infected subjectsFifty-four HIV-infected subjects were recruited from 3 centers: the University of California at San Francisco (UCSF), the San Francisco General Hospital, and the Hospices Civils de Lyon, France. This study was approved by the Committee for Human Research, UCSF. Subjects were enrolled consecutively, and the only inclusion criterion was a confirmed HIVpositive serology and a written informed consent. The following conditions, which can nonspecifically affect blood cell counts, were used as exclusion criteria: previous cytotoxic chemotherapy, splenectomy, hypersplenism, and blood transfusion within the past 4 weeks. After inclusion, a full medical history was taken and physic...

The primary CD8+ T cell response of C57BL/6J mice against the 28 known epitopes of lymphocytic choriomeningitis virus (LCMV) is associated with a clear immunodominance hierarchy whose mechanism has yet to be defined. To evaluate the role of epitope competition in immunodominance, we manipulated the number of CD8+ T cell epitopes that could be recognized during LCMV infection. Decreasing epitope numbers, using a viral variant lacking dominant epitopes or C57BL/6J mice lacking H-2Kb, resulted in minor response increases for the remaining epitopes and no new epitopes being recognized. Increasing epitope numbers by using F1 hybrid mice, delivery by recombinant vaccinia virus, or epitope delivery as a pool in IFA maintained the overall response pattern; however, changes in the hierarchy did become apparent. MHC binding affinity of these epitopes was measured and was found to not strictly predict the hierarchy since in several cases similarly high binding affinities were associated with differences in immunodominance. In these instances the naive CD8+ T cell precursor frequency, directly measured by tetramer staining, correlated with the response hierarchy seen after LCMV infection. Finally, we investigated an escape mutant of the dominant GP33-41 epitope that elicited a weak response following LCMV variant virus infection. Strikingly, dominance loss likely reflects a substantial reduction in frequencies of naive precursors specific for this epitope. Thus, our results indicate that an intrinsic property of the epitope (MHC binding affinity) and an intrinsic property of the host (naive precursor frequency) jointly dictate the immunodominance hierarchy of CD8+ T cell responses.