Type III interferons (IFN-lambdas(λ)) are important cytokines that inhibit viruses and modulate immune responses by acting through a unique IFN-λR1/IL-10RB heterodimeric receptor. Until now, the primary antiviral function of IFN-λs has been proposed to be at anatomical barrier sites. Here, we examine the regulation of IFN-λR1 expression and measure the downstream effects of IFN-λ3 stimulation in primary human blood immune cells, compared with lung or liver epithelial cells. IFN-λ3 directly bound and upregulated IFN-stimulated gene (ISG) expression in freshly purified human B cells and CD8 + T cells, but not monocytes, neutrophils, natural killer cells, and CD4 + T cells. Despite similar IFNLR1 transcript levels in B cells and lung epithelial cells, lung epithelial cells bound more IFN-λ3, which resulted in a 50-fold greater ISG induction when compared to B cells. The reduced response of B cells could be explained by higher expression of the soluble variant of IFN-λR1 (sIFN-λR1), which significantly reduced ISG induction when added with IFN-λ3 to peripheral blood mononuclear cells or liver epithelial cells. T-cell receptor stimulation potently, and specifically, upregulated membrane-bound IFNLR1 expression in CD4 + T cells, leading to greater antiviral gene induction, and inhibition of human immunodeficiency virus type 1 infection. Collectively, our data demonstrate IFN-λ3 directly interacts with the human adaptive immune system, unlike what has been previously shown in published mouse models, and that type III IFNs could be potentially utilized to suppress both mucosal and blood-borne viral infections.

The nuclear orphan receptors NR4A1, NR4A2, and NR4A3 are immediate early genes that are induced by various signals. They act as transcription factors and their activity is not regulated by ligand binding and are thus regulated via their expression levels. Their expression is transiently induced in T cells by triggering of the T cell receptor following antigen recognition during both thymic differentiation and peripheral T cell responses. In this review, we will discuss how NR4A family members impact different aspects of the life of a T cell from thymic differentiation to peripheral response against infections and cancer.

Several unique waves of γδ T cells are generated solely in the fetal/neonatal thymus, whereas additional γδ T cell subsets are generated in adults. One intriguing feature of γδ T cell development is the coordination of differentiation and acquisition of effector function within the fetal thymus; however, it is less clear whether this paradigm holds true in adult animals. In this study, we investigated the relationship between maturation and thymic export of adult-derived γδ thymocytes in mice. In the Rag2pGFP model, immature (CD24+) γδ thymocytes expressed high levels of GFP whereas only a minority of mature (CD24−) γδ thymocytes were GFP+. Similarly, most peripheral GFP+ γδ T cells were immature. Analysis of γδ recent thymic emigrants (RTEs) indicated that most γδ T cell RTEs were CD24+ and GFP+, and adoptive transfer experiments demonstrated that immature γδ thymocytes can mature outside the thymus. Mature γδ T cells largely did not recirculate to the thymus from the periphery; rather, a population of mature γδ thymocytes that produced IFN-γ or IL-17 remained resident in the thymus for at least 60 d. These data support the existence of two populations of γδ T cell RTEs in adult mice: a majority subset that is immature and matures in the periphery after thymic emigration, and a minority subset that completes maturation within the thymus prior to emigration. Additionally, we identified a heterogeneous population of resident γδ thymocytes of unknown functional importance. Collectively, these data shed light on the generation of the γδ T cell compartment in adult mice.

Highly self-reactive T cells are censored from the repertoire by both central and peripheral tolerance mechanisms upon receipt of high-affinity TCR signals. Clonal deletion is considered a major driver of central tolerance; however, other mechanisms such as induction of regulatory T cells and functional impairment have been described. An understanding of the interplay between these different central tolerance mechanisms is still lacking. We previously showed that impaired clonal deletion to a model tissue-restricted antigen (TRA) did not compromise tolerance. In this study, we determined that T cells that failed clonal deletion in this model were rendered functionally impaired in the thymus. PD-1 was induced in the thymus and established cell-intrinsic tolerance to TRA in CD8+ thymocytes independently of clonal deletion. PD-1 signaling in developing thymocytes was sufficient to induce tolerance but was dispensable for the initial maintenance of tolerance in the periphery. We showed that chronic exposure to high affinity antigen supported the long-term maintenance of tolerance in this model. Taken together, our study identifies a role for PD-1 in establishing central tolerance in autoreactive T cells that escape clonal deletion and sheds light on potential mechanisms of action of anti-PD-1 pathway immune checkpoint blockade and the development of immune-related adverse events.Significance StatementThe establishment of T cell tolerance is critical to prevent autoimmune diseases. Apoptosis of highly self-reactive thymocytes is an important mechanism that enforces central tolerance. However, not all self-reactive thymocytes undergo apoptosis during development, and the fate of cells that evade this process is under-examined. Using bone marrow chimera, adoptive transfer, and thymic transplant experiments, we found acute PD-1 signaling is required to establish tolerance to tissue-restricted antigen (TRA) independently of clonal deletion. This tolerance is maintained by chronic exposure to tolerizing antigen but persists in the absence of PD-1 until late time points. Overall, this study identifies a role for PD-1 in establishing central tolerance, and it provides insight into the mechanism of PD-1 pathwaytargeting cancer immunotherapies.

Type III interferons (IFN-lambdas(λ)) are the most recently discovered interferon cytokine family that inhibit viruses by signaling through a unique IFN-λR1/IL-10RB heterodimeric receptor. Until now, IFN-λs were thought to primarily act on anatomical barrier epithelial cells, neutrophils and a subset of dendritic cells, although the majority of studies have been performed in mice. Here, we examine regulation of IFN-λR1 expression and downstream effects of IFN-λ3 stimulation of primary human blood immune cells and compare them to lung or liver epithelial cells. IFN-λ3 directly bound and upregulated IFN-stimulated gene (ISG) expression in freshly purified human B cells and CD8+ T cells, but not monocytes, neutrophils, natural killer cells and CD4+ T cells. Despite similar IFNLR1 transcript levels in B cells and lung epithelial cells, lung epithelial cells bound more IFN-λ3, which resulted in a 50-fold greater ISG induction when compared to B cells. The reduced response of B cells could be explained by the higher expression of the soluble splice variant of IFN-λR1, which inhibited ISG induction when added with IFN-λ3 to peripheral blood mononuclear cells. Human CD4+ T cells gained responsiveness to IFN-λ3 upon T-cell receptor stimulation since activation signals potently, and specifically upregulated membrane-bound IFN-λR1 expression. Importantly, IFN-λ3 treatment of activated CD4+ T cells caused a significant decrease in human immunodeficiency virus-1 (HIV-1) infection. Collectively, our data demonstrate that IFN-λ3 directly interacts with the human adaptive immune system, and thus can promote antiviral immunity at mucosal and peripheral sites, unlike what has been previously shown in published mouse models.