Uncoupling protein 2 regulates metabolic reprogramming and fate of antigen-stimulated CD8+ T cells.

Adoptive cell therapy (ACT) employing ex vivo-generated tumor antigen-specific CD8+ T cells shows tumor efficacy when the transferred cells possess both effector and memory functions. New strategies based on understanding of mechanisms that balance CD8+ T cell differentiation toward effector and memory responses are highly desirable. Emerging information confirms a central role for antigen-induced metabolic reprogramming in CD8+ T cell differentiation and clonal expansion.

β-Catenin in dendritic cells exerts opposite functions in cross-priming and maintenance of CD8+ T cells through regulation of IL-10.

Recent studies have demonstrated that β-catenin in DCs serves as a key mediator in promoting both CD4(+) and CD8(+) T-cell tolerance, although how β-catenin exerts its functions remains incompletely understood. Here we report that activation of β-catenin in DCs inhibits cross-priming of CD8(+) T cells by up-regulating mTOR-dependent IL-10, suggesting blocking β-catenin/mTOR/IL-10 signaling as a viable approach to augment CD8(+) T-cell immunity. However, vaccination of DC-β-catenin(-/-) (CD11c-specific deletion of β-catenin) mice surprisingly failed to protect them against tumor challenge.

β-catenin mediates tumor-induced immunosuppression by inhibiting cross-priming of CD8⁺ T cells.

Whereas CD8⁺ T cells are essential for anti-tumor immunity, tumors often evade CD8⁺ T cell surveillance by immunosuppression. As the initiators of antigen-specific immune responses, DCs are likely to play a central role in regulating the balance between immunity and tolerance to tumor antigens and are specialized in their ability to cross-present exogenous tumor antigens on MHC class I molecules to initiate CD8⁺ T cell immunity. However, it remains unclear whether and how tumors modulate DC functions to suppress CD8⁺ T cell responses.

A unique form of haptoglobin produced by murine hematopoietic cells supports B-cell survival, differentiation and immune response.

Haptoglobin (Hp), an acute phase reactant and major hemoglobin-binding protein, has a unique role in host immunity. Previously, we demonstrated that Hp-deficient C57BL/6J mice exhibit stunted development of mature T- and B-cells resulting in markedly lower levels of antigen-specific IgG. The current study identified leukocyte-derived pro-Hp as a relevant mediator of an optimal immune response.

Rapamycin: A rheostat for CD8(+) T-cell-mediated tumor therapy.

Vaccines that generate Ag-specific CD8(+) T-cell responses of appropriate quality, magnitude and duration are highly desirable. The ability of mTOR to regulate CD8(+) T-cell functional differentiation must be exploited for clinical benefit. In a recent paper, we report that varying the regimen of rapamycin administration regulates viral vaccine-induced CD8(+) T-cell responses for tumor immunity.

Transcription factor Foxo1 represses T-bet-mediated effector functions and promotes memory CD8(+) T cell differentiation.

The evolutionary conserved Foxo transcription factors are important regulators of quiescence and longevity. Although, Foxo1 is known to be important in regulating CD8(+) T cell trafficking and homeostasis, its role in functional differentiation of antigen-stimulated CD8(+) T cells is unclear. Herein, we demonstrate that inactivation of Foxo1 was essential for instructing T-bet transcription factor-mediated effector differentiation of CD8(+) T cells.

Regulating mammalian target of rapamycin to tune vaccination-induced CD8(+) T cell responses for tumor immunity.

Vaccine strategies aimed at generating CD8(+) T cell memory responses are likely to show augmented efficacy against chronic challenges like tumor. The abundance in variety of memory CD8(+) T cells behooves development of vaccine strategies that generate distinct memory responses and evaluate them for tumor efficacy. In this study, we demonstrate the ability of a variety of rapamycin treatment regimens to regulate virus vaccination-induced CD8(+) T cell memory responses and tumor efficacy.

A central role for mTOR kinase in homeostatic proliferation induced CD8+ T cell memory and tumor immunity.

The cell-intrinsic mechanisms guiding naive CD8+ T cells for clonal expansion and memory generation via homeostatic proliferation (HP) are unclear. Here, we have shown that HP of naive CD8+ T cells requires IL-7-, but not IL-15-induced mTOR kinase activation. HP-induced mTOR enhances transcription factor T-bet for functional maturation and CD122 expression, which sensitizes for an IL-15-dependent memory transition by favoring transcription factor Eomesodermin over T-bet.

Fine-tuning CD8(+) T cell functional responses: mTOR acts as a rheostat for regulating CD8(+) T cell proliferation, survival and differentiation?

Naïve CD8(+) T cells are instructed by antigen, co-stimulatory molecules and cytokines to undergo proliferation, clonal expansion and differentiation for effector and memory functions. The integration of extracellular instructions induces coordinated signaling cascades and transcriptional programs to determine CD8(+) T cell functional fate. Although, an important role for the energy sensitive kinase-mammalian target of rapamycin (mTOR) in regulating T cell proliferation and cell survival instep with cellular metabolic status has been demonstrated, emerging information indicates that mTOR also acts as a critical regulator of effector and memory functional fates in CD8(+) T cells.

NY-ESO-1 protein glycosylated by yeast induces enhanced immune responses.

Vaccine strategies that target dendritic cells to elicit potent cellular immunity are the subject of intense research. Here we report that the genetically engineered yeast Saccharomyces cerevisiae, expressing the full-length tumour-associated antigen NY-ESO-1, is a versatile host for protein production. Exposing dendritic cells (DCs) to soluble NY-ESO-1 protein linked to the yeast a-agglutinin 2 protein (Aga2p) protein resulted in protein uptake, processing and MHC class I cross-presentation of NY-ESO-1-derived peptides.

The mTOR kinase determines effector versus memory CD8+ T cell fate by regulating the expression of transcription factors T-bet and Eomesodermin.

The mechanisms underpinning integration of instructions that program naive CD8+ T cells for effector and/or memory differentiation are not well understood. Herein, we demonstrate that interleukin-12 (IL-12) enhanced and sustained antigen and costimulatory molecule (B7.1)-induced mTOR kinase activity in naive CD8+ (OT-I) T cells via phosphoinositide 3-kinase and STAT4 transcription factor pathways.

Regulating functional cell fates in CD8 T cells.

The attributes of specificity and memory enable CD8(+) T cells to provide long-lasting protection against a variety of challenges. Although, the importance of CD8(+) T cells for protection against intracellular infections and transformation is well-established, the functional type; effector phenotypes (Tc1, Tc2, Tc17 and/or Tcreg) and/or memory (effector or central), of CD8(+) T cells most desirable for tumor immunity is not established. To determine the tumor efficacy of various effector types and/or memory CD8 T cells, it is imperative to better understand intrinsic and extrinsic factors that regulate CD8(+) T cell differentiation and use this information to generate and test distinct functional cell types in tumor models.

Antigen-induced Erk1/2 activation regulates Ets-1-mediated sensitization of CD8+ T cells for IL-12 responses.

The presence of IL-12 during antigen stimulation instructs naive CD8+ T cells for long-term effector responses, but their mechanisms of collaboration are not understood completely. Herein, we report that CD8+ T cells (OT-I T cells) stimulated with antigen for a longer duration show enhanced sensitization to IL-12 as a result of Erk1/2-dependent, increased Ets-1 phosphorylation and subsequent increases in IL-12Rbeta2 expression. Correspondingly, naive OT-I T cells stimulated by antigen for a longer duration in the presence of IL-12, irrespective of frequency of APCs, show robust effector maturation and mount long-term antigen-recall responses upon adoptive transfer.

Angiostatic activity of the antitumor cytokine interleukin-21.

Interleukin-21 (IL-21) is a recently described immunoregulatory cytokine. It has been identified as a very potent immunotherapeutic agent in several cancer types in animal models, and clinical studies are ongoing. IL-21 belongs to the type I cytokine family of which other members, ie, IL-2, IL-15, and IL-4, have been shown to exert activities on vascular endothelial cells (ECs).

The acute phase protein haptoglobin regulates host immunity.

The contribution of acute phase plasma proteins to host immune responses remains poorly characterized. To better understand the role of the acute phase reactant and major hemoglobin-binding protein haptoglobin (Hp) on the function of immune cells, we generated Hp-deficient C57BL/6J mice. These mice exhibit stunted development of lymphoid organs associated with lower counts of mature T and B cells in the blood and secondary lymphoid compartments.

Recognition of naturally processed and ovarian cancer reactive CD8+ T cell epitopes within a promiscuous HLA class II T-helper region of NY-ESO-1.

NY-ESO-1 is frequently expressed in epithelial ovarian cancer (EOC) and elicits spontaneous humoral and cellular immune responses in a proportion of EOC patients. The identification of NY-ESO-1 peptide epitopes with dual HLA-class I and class II specificities might be useful in vaccination strategies for generating cognate CD4+ T cell help to augment CD8+ T cell responses. Here, we describe two novel NY-ESO-1-derived MHC class I epitopes from EOC patients with spontaneous humoral immune response to NY-ESO-1.

IL-12-programmed long-term CD8+ T cell responses require STAT4.

Immunological adjuvants activate innate immune cells for Ag presentation and elicitation of cytokines like IL-12 that promote T cell expansion and effector differentiation. An important but elusive aim for most immunization strategies is to produce memory T cells that provide durable immunity. Recent evidence demonstrates that the context of Ag presentation instructionally programs T cells for short- and long-term responses.

Aspergillus fumigatus extract differentially regulates antigen-specific CD4+ and CD8+ T cell responses to promote host immunity.

Invasive aspergillosis is a major cause of morbidity and mortality in the severely immunocompromised. The paucity of information about the mechanisms by which Aspergillus-derived factors regulate antigen-specific T cell responses in vivo poses a significant hurdle for devising effective immunization strategies to treat or prevent aspergillosis. By monitoring adoptively transferred T cell receptor transgenic, naive CD4+ (OT-II) and CD8+ (OT-I) T cells specific for distinct peptides of a nominal antigen, chicken ovalbumin (OVA), we demonstrate that sensitization with Aspergillus fumigatus (Af) extract plus OVA protein considerably enhances OT-I and OT-II T cell activation, which results in clonal expansion, primarily as a result of increased proliferation.

Increased level and longevity of protective immune responses induced by DNA vaccine expressing the HIV-1 Env glycoprotein when combined with IL-21 and IL-15 gene delivery.

We investigated the ability of a plasmid-derived IL-21 delivered alone or in combination with the IL-15 gene to regulate immune responses to the HIV-1 envelope (Env) glycoprotein induced by DNA vaccination. Mice were injected with the gp140DeltaCFI(HXB2/89.6) vector expressing a modified Env glycoprotein with C-terminal mutations intended to mimic a fusion intermediate, in which the most divergent region encoding the variable V1, V2, and V3 domains of CXCR4-tropic HxB2 virus was replaced with the dual-tropic 89.

CD4-dependent potentiation of a high molecular weight-melanoma-associated antigen-specific CTL response elicited in HLA-A2/Kb transgenic mice.

The human high m.w.-melanoma-associated Ag (HMW-MAA) is an attractive target for the immunotherapy of melanoma, due to its relatively high expression in a high percentage of melanoma lesions and its restricted distribution in normal tissues.

IL-21 enhances and sustains CD8+ T cell responses to achieve durable tumor immunity: comparative evaluation of IL-2, IL-15, and IL-21.

Cytokines that use the common receptor gamma-chain for regulating CD8(+) T cell responses to Ag include IL-2, IL-15, and the recently identified IL-21. The ability of these cytokines to regulate antitumor activity in mice has generated considerable interest in understanding their mode of action. In this study we compare the abilities of IL-2, IL-15, and IL-21 to stimulate immunity against tumors in a syngeneic thymoma model.

Alteration of cell surface sialylation regulates antigen-induced naive CD8+ T cell responses.

The strength of interactions with APC instructs naive T cells to undergo programmed expansion and differentiation, which is largely determined by the peptide affinity and dose as well as the duration of TCR ligation. Although, most ligands mediating these interactions are terminally sialylated, the impact of the T cell sialylation status on Ag-dependent response remains poorly understood. In this study, by monitoring TCR transgenic CD8+ T cells, OT-I, we show that biochemical desialylation of naive OT-I T cells increases their sensitivity for agonist as well as partial agonist peptides.