Although many self-reactive T cells are eliminated by negative selection in the thymus, some of these cells escape into the periphery, where they must be controlled by additional mechanisms. However, the molecular mechanisms underlying peripheral T cell tolerance and its maintenance remain largely undefined. In this study, we report that sirtuin 1 (Sirt1), a type III histone deacetylase, negatively regulates T cell activation and plays a major role in clonal T cell anergy in mice. In vivo, we found that loss of Sirt1 function resulted in abnormally increased T cell activation and a breakdown of CD4 + T cell tolerance. Conversely, upregulation of Sirt1 expression led to T cell anergy, in which the activity of the transcription factor AP-1 was substantially diminished. Furthermore, Sirt1 interacted with and deacetylated c-Jun, yielding an inactive AP-1 factor. In addition, Sirt1-deficient mice were unable to maintain T cell tolerance and developed severe experimental allergic encephalomyelitis as well as spontaneous autoimmunity. These findings provide insight into the molecular mechanisms of T cell activation and anergy, and we suggest that activators of Sirt1 may be useful as therapeutic agents for the treatment and/or prevention of autoimmune diseases.

Rapid memory CD4+ T helper 2 (TH2) cell activation during allergic inflammation requires their recruitment into the affected tissue. Here we demonstrate that group 2 innate lymphoid cells (ILC2) play a critical role in memory TH2 cell responses, with targeted ILC2 depletion profoundly impairing TH2 cell localization to the lungs and skin of sensitized mice after allergen re-challenge. ILC2-derived interleukin-13 (IL-13) is critical for eliciting IRF4+CD11b+CD103− dendritic cells (DCs) to produce the TH2 cell-attracting chemokine CCL17. Consequently, the sentinel function of DCs is contingent on ILC2s for the generation of an efficient memory TH2 cell response. These results elucidate a key new innate mechanism in the regulation of the immune memory response to allergens.

The autoreactive T cells that escape central tolerance and form the peripheral self-reactive repertoire determine both susceptibility to autoimmune disease and the epitope dominance of a specific autoantigen. SJL (H-2s) mice are highly susceptible to the induction of experimental autoimmune encephalomyelitis (EAE) with myelin proteolipid protein (PLP). The two major encephalitogenic epitopes of PLP (PLP 139–151 and PLP 178–191) bind to IAs with similar affinity; however, the immune response to the PLP 139–151 epitope is always dominant. The immunodominance of the PLP 139–151 epitope in SJL mice appears to be due to the presence of expanded numbers of T cells (frequency of 1/20,000 CD4+ cells) reactive to PLP 139–151 in the peripheral repertoire of naive mice. Neither the PLP autoantigen nor infectious environmental agents appear to be responsible for this expanded repertoire, as endogenous PLP 139–151 reactivity is found in both PLP-deficient and germ-free mice. The high frequency of PLP 139–151-reactive T cells in SJL mice is partly due to lack of thymic deletion to PLP 139–151, as the DM20 isoform of PLP (which lacks residues 116–150) is more abundantly expressed in the thymus than full-length PLP. Reexpression of PLP 139–151 in the embryonic thymus results in a significant reduction of PLP 139–151-reactive precursors in naive mice. Thus, escape from central tolerance, combined with peripheral expansion by cross-reactive antigen(s), appears to be responsible for the high frequency of PLP 139–151-reactive T cells.

Immunity in the newborn is characterized by minimal Th1 function but an excess of Th2 activity. Since Th1 lymphocytes are important to counter microbes and Th2 cells favor allergies, the newborn faces susceptibility to microbial infections and allergic reactions. Delayed maturation of certain dendritic cells leads to limited IL-12 production during the neonatal period. The Th2 cytokine locus of neonatal CD4+ T cells is epigenetically poised for rapid and robust production of IL-4 and IL-13. Together, these circumstances lead to efficient differentiation of Th2 cells and the expression of an IL-4Rα/IL-13Rα1 heteroreceptor on Th1 cells. Upon rechallenge, Th2 cells rapidly produce IL-4 which utilizes the heteroreceptor to drive apoptosis of Th1 cells yielding the Th2 bias of neonatal immunity.

The role of Th17 cells in type I diabetes (TID) remains largely unknown. Glutamic acid decarboxylase (GAD) sequence 206–220 (designated GAD2) represents a late-stage epitope, but GAD2-specific T cell receptor transgenic T cells producing interferon γ (IFNγ) protect against passive TID. Because IFNγ is known to inhibit Th17 cells, effective presentation of GAD2 peptide under noninflammatory conditions may protect against TID at advanced disease stages. To test this premise, GAD2 was genetically incorporated into an immunoglobulin (Ig) molecule to magnify tolerance, and the resulting Ig-GAD2 was tested against TID at different stages of the disease. The findings indicated that Ig-GAD2 could not prevent TID at the preinsulitis phase, but delayed TID at the insulitis stage. More importantly, Ig-GAD2 sustained both clearance of pancreatic cell infiltration and β-cell division and restored normoglycemia when given to hyperglycemic mice at the prediabetic stage. This was dependent on the induction of splenic IFNγ that inhibited interleukin (IL)-17 production. In fact, neutralization of IFNγ led to a significant increase in the frequency of Th17 cells, and the treatment became nonprotective. Thus, IFNγ induced by an adjuvant free antigen, contrary to its usual inflammatory function, restores normoglycemia, most likely by localized bystander suppression of pathogenic IL-17–producing cells.

Primary neonatal T cell responses comprise both T helper (

Primary neonatal Th1 cells develop alongside of Th2 upon priming of the newborn but undergo apoptosis upon recall with antigen. These Th1 cells were isolated, and their death was correlated with elevated IL-13Ralpha1 chain expression. Strikingly, neutralization of Th2s' IL-4 reduced apoptosis, sustained recall responses, and the live Th1 cells displayed a decrease in IL-13Ralpha1 expression. Blockade of IL-13Ralpha1 or IL-4Ralpha also restores recall and secondary Th1 responses. Adult T cells primed within the neonatal environment did not upregulate IL-13Ralpha1 chain or undergo apoptosis and developed recall Th1 responses. These observations indicate that developmental expression of IL-13Ralpha1 along with IL-4Ralpha provides a receptor through which IL-4 induces death of Th1 cells and skews neonatal immunity toward Th2.

We characterized the structural forms of the human immunodeficiency virus env-encoded proteins with a panel of monoclonal and polyclonal antibodies. Western blot (immunoblot) assays with antibodies specific for gp4l invariably recognized a major component of 160 kilodaltons and a less intense component of 120 kilodaltons in viral lysates. We demonstrated that these species are noncovalently associated tetramers and trimers of gp4l which represent the native form of this protein in virions. These complexes were stable when boiled in the presence of low concentrations of sodium dodecyl sulfate but were dissociated to gp4l monomers at high sodium dodecyl sulfate concentrations. Moreover, two human monoclonal antibodies preferentially recognized the oligomeric complexes over monomeric gp4l in Western blots, indicating the presence of epitopes recognized by the human immune system on the gp4l multimers which are not efficiently expressed by the dissociated monomers. The demonstration of the existence of multimeric env complexes and the enhanced and altered antigenicity of such multimers may be relevant to the design of subunit and recombinant human immunodeficiency virus env vaccines.