Programmed cell death-1 (PD-1) targeted therapies enhance T cell responses and show efficacy in multiple cancers but the role of costimulatory molecules in this T cell rescue remains elusive. Here we demonstrate that the CD28/B7 costimulatory pathway is essential for effective PD-1 therapy during chronic viral infection of mice. Conditional gene deletion showed a cell-intrinsic requirement of CD28 for CD8 T cell proliferation after PD-1 blockade. B7-costimulation was also necessary for effective PD-1 therapy in tumor-bearing mice. In addition, we found that CD8 T cells proliferating in blood after PD-1 therapy of lung cancer patients were predominantly CD28 positive. Taken together these data demonstrate CD28-costimulation requirement for CD8 T cell rescue and suggest an important role for CD28/B7 pathway in PD-1 therapy of cancer patients.

SUMMARY Regulatory T cells (Treg cells) are required for immune homeostasis. Chromatin remodeling is essential for establishing diverse cellular identities, but how the epigenetic program in Treg cells is maintained throughout the dynamic activation process remains unclear. Here we have shown that CD28 co-stimulation, an extracellular cue intrinsically required for Treg cell maintenance, induced the chromatin-modifying enzyme, Ezh2. Treg-specific ablation of Ezh2 resulted in spontaneous autoimmunity with reduced Foxp3+ cells in non-lymphoid tissues and impaired resolution of experimental autoimmune encephalomyelitis. Utilizing a model designed to selectively deplete wild-type Treg cells in adult mice co-populated with Ezh2-deficient Treg cells, Ezh2-deficient cells were destabilized and failed to prevent autoimmunity. After activation, the transcriptome of Ezh2-deficient Treg cells was disrupted, with altered expression of Treg cell lineage genes in a pattern similar to Foxp3-deficient Treg cells. These studies reveal a critical role for Ezh2 in the maintenance of Treg cell identity during cellular activation.

Tregs expressing the transcription factor FOXP3 are critical for immune homeostasis. The costimulatory molecule CD28 is required for optimal activation and function of naive T cells; however, its role in Treg function has been difficult to dissect, as CD28 is required for thymic Treg development, and blockade of CD28-ligand interactions has confounding effects in trans on nonregulatory cells. To address this question, we created Treg-specific Cd28 conditional knockout mice. Despite the presence of normal numbers of FOXP3 + cells, these animals accumulated large numbers of activated T cells, developed severe autoimmunity that primarily affected the skin and lungs, and failed to appropriately resolve induced experimental allergic encephalomyelitis. This in vivo functional impairment was accompanied by dampened expression of CTLA-4, PD-1, and CCR6. Disease occurrence was not due to subversion of Cd28-deficient Tregs into pathogenic cells, as complementation with normal Tregs prevented disease occurrence. Interestingly, in these "competitive" environments, Cd28-deficient Tregs exhibited a pronounced proliferative/survival disadvantage. These data demonstrate clear postmaturational roles for CD28 in FOXP3 + Tregs and provide mechanisms which we believe to be novel to explain how interruption of CD28-ligand interactions may enhance immune responses independent of effects on thymic development or on other cell types.

Mutations in the tumor-suppressor gene phosphatase and tensin homolog deleted on chromosome 10 (Pten) are associated with multiple cancers in humans, including T cell malignancies. Targeted deletion of Pten in T cells induces both a disseminated "mature phenotype" lymphoma and a lymphoproliferative autoimmune syndrome in mice. Here, we have shown that these two diseases are separable and mediated by T lineage cells of distinct developmental stages. Loss of PTEN was found to be a powerful driver of lymphomagenesis within the thymus characterized by overexpression of the c-myc oncogene. In an otherwise normal thymic environment, PTEN-deficient T cell lymphomas invariably harbored RAG-dependent reciprocal t(14:15) chromosomal translocations involving the T cell receptor alpha/delta locus and c-myc, and their survival and growth was TCR dependent, but Notch independent. However, lymphomas occurred even if TCR recombination was prevented, although these lymphomas were less mature, arose later in life, and, importantly, were dependent upon Notch pathways to upregulate c-myc expression. In contrast, using the complementary methods of early thymectomy and adoptive transfers, we found that PTEN-deficient mature T cells were unable to undergo malignant transformation but were sufficient for the development of autoimmunity. These data suggest multiple and distinct regulatory roles for PTEN in the molecular pathogenesis of lymphoma and autoimmunity.

All inorganic cesium lead halide (CsPbX 3 , X = Cl, Br, I) perovskite nanocrystals (PeNCs) are synthesized by employing polar solvent controlled ionization (PCI) method in precursors. The new strategy can be easily carried out at room temperature and allow to employ smaller amount of weaker polarity and a broader range of low-boiling low-toxic solvents. The as prepared CsPbX 3 PeNCs reveal tunable emission spectra from 380 to 700 nm and high quantum yields over 80% with narrow full width at half maximum (FWHM). Meanwhile, larger "effective Stokes shifts" of PeNCs in PCI method, which enlarges 200% more than other PeNCs in regular methods, are observed. Most interestingly, the PeNCs growth process is coupling with some typical crystals formations. The main morphologies of CsPbI 3 PeNCs are hybrid of nanorods and nanoparticles. The primary morphologies of CsPbBr x I 3-x and CsPbBr 3 PeNCs are nanowires, which are supposed to have great potentials for applying in laser arrays and highly sensitive photodetector applications. Furthermore, such superior optical is endowed to fabricate white light emitting diodes, which has wide color gamut covering up to 120% of the National Television Systems Committee color standard.

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Induction of specific immune tolerance to grafts remains the sought-after standard following transplantation. Defined by expression of the Foxp3 (forkhead box protein 3) transcription factor, the regulatory T-cell (Treg) lineage has been noted to exert potent immunoregulatory functions that contribute to specific graft tolerance. In this review, we discuss the known signals and pathways which govern Treg development, both in the thymus and in peripheral sites, as well as lineage maintenance and homeostasis. In particular, we highlight the roles of T-cell receptor signaling, CD28 costimulation, and signals through phosphatidyl inositol 3-kinase (PI3K) and related metabolic pathways in multiple aspects of Treg biology.

Inflammatory signals induced during infection regulate T-cell expansion, differentiation, and memory formation. Toll-like receptors (TLRs) are inflammatory mediators that allow innate immune cells to recognize and respond to invading pathogens. In addition to their role in innate immune cells, we have found that signals delivered through the TLR adapter protein myeloid differentiation protein 88 (MyD88) play a critical, T cell-intrinsic role in supporting the survival and accumulation of antigen-specific effector cells after acute viral infection. However, the importance of MyD88-dependent signals in regulating the generation and maintenance of memory T cells remained unclear. To address this, we used a novel, inducible knockout system to examine whether MyD88 is required for optimal memory CD8 T-cell generation and responses after lymphocytic choriomeningitis virus infection. We show that whereas MyD88 is critical for initial T-cell expansion, it is not required for the subsequent differentiation and stable mainte- IntroductionDuring acute viral infection, naive CD8 T cells undergo an initial phase of expansion and differentiation into functional effectors that play an integral role in viral clearance. The expansion phase is typically followed by a period of contraction, during which time the majority of effector T cells undergo apoptosis, and the remaining virus-specific T cells persist as a stable memory population that differs both phenotypically and functionally from the naive T-cell population. These memory CD8 T cells can rapidly differentiate into secondary effectors on subsequent reinfection and confer long-lasting, protective immunity. Thus, developing a better understanding of the signals that regulate the generation, maintenance, and reactivation of memory T cells is central to rational vaccine design.Myeloid differentiation protein 88 (MyD88) is an adaptor protein that is required for signal transduction through most Toll-like receptors (TLRs), as well as the interleukin-1 receptor (IL-1R) family. 1 TLR ligands that are released during infection are known agonists of MyD88-dependent pathways in innate immune cells, inducing activation, costimulatory molecule up-regulation, and inflammatory cytokine production, which serve to promote effective adaptive immune responses. 2,3 In addition to this indirect role, we and others have shown previously that MyD88 plays a critical, T cell-intrinsic role in regulating the survival and accumulation of antigen-specific effector T cells after acute viral infection. [4][5][6] Specifically, in the absence of MyD88, the number of effector CD8 T cells at the peak of the response and the number of antigen-specific memory T cells that persist are greatly reduced. It is well-established that the magnitude of the initial clonal burst significantly influences the size of the resulting memory T-cell compartment, 7 suggesting that the reduced number of memory cells that develop in the absence of MyD88 may be a secondary outcome of the role of MyD88 in controlling naive T-ce...