IntroductionRegulatory T cells (Tregs), characterized by high expression of FoxP3, are potent immunomodulators of T-cell activation that suppress proliferation and cytokine secretion by effector T cells. [1][2][3][4][5] Loss of Tregs by either gene deletion of FoxP3 in mice or mutations in humans results in autoimmune disease and the inability to effectively regulate T-cell activation. 6,7 While Tregs play a fundamental role in protection of autoimmunity, their differentiation is tightly linked to the development of IL-17-producing (Th17) cells, a highly pathogenic effector T-cell subset involved in inducing inflammation and autoimmune tissue injury. 8,9 Both loss of Treg function and induction of Th17 cells have been implicated in the pathogenesis of human autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis, Crohn disease, and psoriasis. [10][11][12][13][14] Although Tregs appear to be central in regulating immune responses to self-antigens, mechanisms must be present to rapidly block their suppressive activity and enable immune activation during an acute microbial infection. In such circumstances, antigen-presenting cells (APC) secrete inflammatory cytokines, such as interleukin-1␤ (IL-1␤) and IL-6, which induce the potent effector responses necessary to clear the infection. In this regard, our data and the work of others have demonstrated that IL-1␤ and IL-6 can drive memory CD4 ϩ T cells to secrete 16 , which has been shown to abrogate suppression by Treg cells, 17 also drives Th17 differentiation in naive cells when paired with transforming growth factor ␤ (TGF␤) in mouse 18 or with IL-1␤, interleukin-23 (IL-23), and TGF␤ in human, 19 although the minimal requirements for Th17 differentiation in human are still being defined. 15,[20][21][22] The role of TGF␤ in Th17 development is surprising, given that TGF␤ promotes adaptive Treg differentiation in murine models and enhances FoxP3 expression in the human system. 23 Yet recent studies in mouse have indicated that TGF␤ and IL-6 can induce IL-17 production in Tregs. 24,25 Despite the apparent duality in Treg/Th17 function, it is becoming increasingly clear that these cell subsets share common cytokine signaling pathways.The memory CD4 ϩ CD25 high human Treg lineage can be subdivided into 2 functionally distinct subsets classified by expression of the major histocompatibility complex (MHC) class II dimer human leukocyte antigen-DR (HLA-DR). 26 DR ϩ Tregs do not enter into cell cycle with T-cell receptor (TCR) cross-linking and exhibit immediate contact-dependent suppressor function. In contrast, DR Ϫ Tregs can enter into cell cycle after activation, secrete the inhibitory cytokine interleukin-10 (IL-10) but not the effector cytokine interferon-␥ (IFN␥), and demonstrate delayed kinetics of suppression, requiring 4 to 5 days for maximal inhibition of proliferation of responder CD4 ϩ T cells. 26 We have previously reported that, in cocultures of human Tregs and responder T cells (Tresp) provided with strong TCR stimulation, the Tresp are refrac...

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system associated with demyelination and axonal loss. A whole genome association scan suggested that allelic variants in the CD58 gene region, encoding the costimulatory molecule LFA-3, are associated with risk of developing MS. We now report additional genetic evidence, as well as resequencing and fine mapping of the CD58 locus in patients with MS and control subjects. These efforts identify a CD58 variant that provides further evidence of association with MS (P ‫؍‬ 1.1 ؋ 10 ؊6 , OR 0.82) and the single protective effect within the CD58 locus is captured by the rs2300747 G allele. This protective rs2300747 G allele is associated with a dose-dependent increase in CD58 mRNA expression in lymphoblastic cell lines (P ‫؍‬ 1.1 ؋ 10 ؊10 ) and in peripheral blood mononuclear cells from MS subjects (P ‫؍‬ 0.0037). This protective effect of enhanced CD58 expression on circulating mononuclear cells in patients with MS is supported by finding that CD58 mRNA expression is higher in MS subjects during clinical remission. Functional investigations suggest a potential mechanism whereby increases in CD58 expression, mediated by the protective allele, up-regulate the expression of transcription factor FoxP3 through engagement of the CD58 receptor, CD2, leading to the enhanced function of CD4 ؉ CD25 high regulatory T cells that are defective in subjects with MS.M ultiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system associated with demyelination, axonal loss, and brain atrophy; susceptibility to this disease is affected by both genetic variation and environmental risk factors (1, 2). The initial episode of neurologic dysfunction results in a clinical diagnosis of a clinically isolated demyelinating syndrome (CIS), and a second episode leads to a diagnosis of MS (1). Increasing evidence suggests that activated, autoreactive T cells play a central role in MS pathophysiology, as evidenced by the efficacy of treatments such as Natalizumab (anti-VLA-4 monoclonal antibody) that block lymphocyte egress from the vascular compartment into the CNS (3). Furthermore, the control of activated T cells by natural regulatory CD4 ϩ T cells is impaired in subjects with MS (4). This population of regulatory CD4 ϩ T cells expresses high levels of the IL-2 receptor (CD25) and FoxP3, an important transcription factor for regulatory T cells (4). We have now begun to integrate these immunologic observations with results of our genetic studies in patients with MS.Two novel MS susceptibility loci have recently been identified using a genome-wide association scan approach, and these 2 loci, IL2RA and IL7R, have now been validated in independent subject collections (5-9). In the genome scan, several other loci, including the CD58 locus, displayed suggestive evidence of association with MS susceptibility. Since CD58 (LFA-3) costimulates and enhances T cell receptor signaling by engaging CD2 (10), the CD58 locus is an attractive target for understanding ...

Objective: Mutational signatures provide insights into the biological processes shaping tumor genomes and may inform patient therapy. We sought to define the mutational signatures of i) endometrioid and serous endometrial carcinomas (ECs), stratified into the four molecular subtypes, ii) uterine carcinosarcomas, and iii) matched primary and metastatic ECs. Methods: Whole-exome sequencing MC3 data from primary endometrioid and serous carcinomas (n=232) and uterine carcinosarcomas (n=57) from The Cancer Genome Atlas (TCGA), and matched primary and metastatic ECs (n=61, 26 patients) were reanalyzed, subjected to mutational signature analysis using deconstructSigs, and correlated with clinicopathologic and genomic data. Results: POLE (ultramutated) and MSI (hypermutated) molecular subtypes displayed dominant mutational signatures associated with POLE mutations (15/17 cases) and microsatellite instability (55/65 cases), respectively. Most endometrioid and serous carcinomas of copy-number low (endometrioid) and copy-number high (serous-like) molecular subtypes, and carcinosarcomas displayed a dominant aging-associated signature 1. Only 15% (9/60) of copy-number high (serous-like) ECs had a dominant signature 3 (homologous recombination DNA repair deficiency (HRD)-related), a prevalence significantly lower than that found in high-grade serous ovarian carcinomas (54%, p<0.001) or basal-like breast cancers (46%, p<0.001). Shifts from aging- or POLE- to MSI-related mutational processes were observed in the progression from primary to metastatic ECs in a subset of cases. Conclusions: The mutational processes underpinning ECs vary even among tumors of the same TCGA molecular subtype and in the progression from primary to metastatic ECs. Only a minority of copy-number high (serous-like) ECs display genomics features of HRD and would likely benefit from HRD-directed therapies.