The autoimmune regulator (AIRE) is essential for the establishment of central tolerance and prevention of autoimmunity. Interestingly, different AIRE mutations cause autoimmunity in either recessive or dominant-negative manners. Using engineered mouse models, we establish that some monoallelic mutants, including C311Y and C446G, cause breakdown of central tolerance. By using RNAseq, ATACseq, ChIPseq, and protein analyses, we dissect the underlying mechanisms for their dominancy. Specifically, we show that recessive mutations result in a lack of AIRE protein expression, while the dominant mutations in both PHD domains augment the expression of dysfunctional AIRE with altered capacity to bind chromatin and induce gene expression. Finally, we demonstrate that enhanced AIRE expression is partially due to increased chromatin accessibility of the AIRE proximal enhancer, which serves as a docking site for AIRE binding. Therefore, our data not only elucidate why some AIRE mutations are recessive while others dominant, but also identify an autoregulatory mechanism by which AIRE negatively modulates its own expression.

The processes and mechanisms of virus infection fate decisions that are the result of a dynamic virus-immune system interaction with either an efficient effector response and virus elimination or an alleviated immune response and chronic infection are poorly understood. Here, we characterized the host response to acute and chronic lymphocytic choriomeningitis virus (LCMV) infections by gene coexpression network analysis of time-resolved splenic transcriptomes. First, we found an early attenuation of inflammatory monocyte/macrophage prior to the onset of T cell exhaustion, and second, a critical role of the XCL1-XCR1 communication axis during the functional adaptation of the T cell response to the chronic infection state. These findings not only reveal an important feedback mechanism that couples T cell exhaustion with the maintenance of a lower level of effector T cell response but also suggest therapy options to better control virus levels during the chronic infection phase.

Foxp3+ regulatory T cells (Tregs) are potent suppressor cells, essential for the maintenance of immune homeostasis. Most Tregs develop in the thymus and are then released into the immune periphery. However, some Tregs populate the thymus and constitute a major subset of yet poorly understood cells. Here we describe a subset of thymus recirculating IL18R+ Tregs with molecular characteristics highly reminiscent of tissue-resident effector Tregs. Moreover, we show that IL18R+ Tregs are endowed with higher capacity to populate the thymus than their IL18R– or IL18R–/– counterparts, highlighting the key role of IL18R in this process. Finally, we demonstrate that IL18 signaling is critical for the induction of the key thymus-homing chemokine receptor – CCR6 on Tregs. Collectively, this study provides a detailed characterization of the mature Treg subsets in the mouse thymus and identifies a key role of IL18 signaling in controlling the CCR6-CCL20-dependent migration of Tregs into the thymus.

28 29 ¶ These authors contributed equally to this work. 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 49 50 Upon a viral infection, the host immune system attempts to eradicate the virus. However, 51 once the infection threat seems overwhelming, the infected host actively shuts down effector 52 responses to reduce immunopathology. The price to pay for this is the establishment of a 53 chronic infection that is only partially controlled by a lower level immune response. The 54 genetic networks underlying this infection fate decision and the immune adaptation to the 55 lower level response are not well understood. Here we used an integrated approach of gene 56 coexpression network analysis of time-resolved splenic transcriptomes and immunological 57 analysis to characterize the host response to acute and chronic lymphocytic choriomeningitis 58 virus (LCMV) infections. We found first, an early attenuation of inflammatory 59 monocyte/macrophage prior to the onset of T cell exhaustion and second, a critical role of the 60 XCL1-XCR1 communication axis during the functional adaptation of the T cell response to 61 the chronic infection state. These findings not only reveal an important feedback mechanism 62 that couples T cell exhaustion with the maintenance of a lower level of effector T cell 63 response but also suggest therapy options to better control virus levels during the chronic 64 infection phase. 65 66 Author Summary 67 The outcomes of viral infections are the result of dynamic interplays between infecting 68 viruses and induced host responses. They can be categorized as either acute or chronic 69 depending on temporal virus-host relationships. Chronic infections are associated with 70 immune exhaustion, a partial shut-down of effector responses. The processes underlying 71 infection fate decisions are incompletely understood. Here we analyzed, on a systems level, 72 infection-fate-specific gene signatures and the resulting adaptive processes of the host. We 73 used the well-established lymphocytic choriomeningitis virus infection mouse model which 74has been instrumental to detect many fundamental processes in the virus-immune system 75 crosstalk that are also relevant in human infections. We show an early attenuation of 76 macrophage-mediated inflammation and an involvement of cross-presenting dendritic cells in 77 the maintenance of an antiviral cytotoxic T cell response and virus control in the chronic 78 infection phase. Together our data demonstrate a delicate adaptation process towards a 79 chronic virus infection with both immunosuppressive and immunostimulatory processes. We 80 fill a knowledge gap regarding the mechanisms of effector T cell maintenance and provide a 81 new rational for targeted therapeutic vaccination. 82 83

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