Glucocorticoid-induced TNFR-related protein (GITR) is a costimulatory molecule with diverse effects on effector T cells and regulatory T cells (Tregs), but the underlying mechanism remains poorly defined. Here we demonstrate that GITR ligation subverts the induction of Foxp3+ Tregs and directs the activated CD4+ T cells to Th9 cells. Such GITR-mediated iTreg to Th9 induction enhances anti-tumour immunity in vivo. Mechanistically, GITR upregulates the NF-κB family member p50, which recruits histone deacetylases to the Foxp3 locus to produce a ‘closed' chromatin structure. Furthermore, GITR ligation also activates STAT6, and STAT6 renders Il9 locus accessible via recruitment of histone acetyltransferase p300, and together with inhibition of Foxp3, GITR induces strong Th9 responses. Thus, Th9 cells and iTregs are developmentally linked and GITR can subvert tolerogenic conditions to boost Th9 immunity.

Immunological memory specific to previously encountered antigens is a cardinal feature of adaptive lymphoid cells. However, it is unknown whether innate myeloid cells retain memory of prior antigenic stimulation and respond to it more vigorously on subsequent encounters. In this work, we show that murine monocytes and macrophages acquire memory specific to major histocompatibility complex I (MHC-I) antigens, and we identify A-type paired immunoglobulin-like receptors (PIR-As) as the MHC-I receptors necessary for the memory response. We demonstrate that deleting PIR-A in the recipient or blocking PIR-A binding to donor MHC-I molecules blocks memory and attenuates kidney and heart allograft rejection. Thus, innate myeloid cells acquire alloantigen-specific memory that can be targeted to improve transplant outcomes.

OX40 is a T cell costimulatory molecule that belongs to the TNFR superfamily. In the absence of immune activation, OX40 is selectively expressed by Foxp3+ Tregs, but not by resting conventional T cells. The exact role of OX40 in Treg homeostasis and function remains incompletely defined. Here, we demonstrate that OX40 engagement in vivo in naïve mice induces initial expansion of Foxp3+ Tregs, but the expanded Tregs have poor suppressive function and exhibit features of exhaustion. We also show that OX40 enables the activation of the Akt and Stat5 pathways in Tregs, resulting in transient proliferation of Tregs and reduced levels of Foxp3 expression. This creates a state of relative IL-2 deficiency in naïve mice that further impacts Tregs. This exhausted Treg phenotype can be prevented by exogenous IL-2, as both OX40 and IL-2 agonists drive further expansion of Tregs in vivo. Importantly, Tregs expanded by both OX40 and IL-2 agonists are potent suppressor cells, and in a heart transplant model, they promote long-term allograft survival. Our data uncover a novel role for OX40 in promoting immune tolerance and may have important clinical implications.

Both innate and adaptive immune cells are involved in the allograft response. But how the innate immune cells respond to allotransplants remains poorly defined. In the present study, we examined the role of NK cells and macrophages in recognizing and rejecting allogeneic cells in vivo. We found that in naïve mice NK cells are the primary effector cells in killing of allogeneic cells via “the missing self” recognition. However, in alloantigen pre-sensitized mice, NK cells are dispensable. Instead, macrophages become alloreactive and readily recognize and reject allogeneic non-self. This effect requires help from activated CD4+ T cells and involves CD40/CD40L engagement, as blocking CD40/CD40L interactions prevents macrophage mediated rejection of allogeneic cells. Conversely, actively stimulating CD40 triggers macrophage-mediated rejection in the absence of CD4+ T cells. Importantly, alloantigen primed and CD4+ T cell-helped macrophages (licensed macrophages) exhibit potent regulatory function in vivo in an acute GVHD model. Together, our data uncover an important role for macrophages in the alloimmune response and may have important clinical implications.

No abstract

Axis inhibition protein 2 (Axin2) is a negative regulator of the canonical Wnt/β-catenin signaling pathway, and functions as a tumor suppressor in a number of human cancers. Previous pilot studies have suggested an association between Axin2 exon1 148 (rs2240308) SNP polymorphism and risk for lung cancer. In the present study, we aimed to investigate the Axin2 exon1 148 polymorphism and its association with lung cancer susceptibility in Han Chinese population. The Axin2 exon1 148 SNP was genotyped in 555 controls and 520 lung cancer patients using TaqMan SNP Genotyping Assays. Unconditional logistic regression analysis was used to calculate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). We observed that the genotype frequencies of TC, TT, and CC were significantly different between controls and cases (χ(2) = 6.849, P = 0.03256, df = 2). Subjects carrying T allele (TC + TT genotypes) had decreased susceptibility to lung cancer as compared to those carrying CC genotype (OR = 0.733, 95% CI = 0.5726-0.9393, P = 0.01382). No significant association was found between rs2240308 polymorphism and histological subtypes of lung cancers. Findings from this study suggest that Axin2 exon1 T148C polymorphism (rs2240308) contributes to increased susceptibility to lung cancer in Chinese population. This further implicates Axin2 as a lung cancer-related gene.

No abstract

No abstract