Detection and Characterization of CD8+ Autoreactive Memory Stem T Cells in Patients With Type 1 Diabetes

Stem memory T cells (Tscm) constitute the earliest developmental stage of memory T cells, displaying stem cell–like properties, such as self-renewal capacity. Their superior immune reconstitution potential has sparked interest in cancer immune therapy, vaccine development, and immune reconstitution, whereas their role in autoimmunity is largely unexplored. Here we show that autoreactive CD8+ Tscm specific for β-cell antigens GAD65, insulin, and IGRP are present in patients with type 1 diabetes (T1D). In vitro, the generation of autoreactive Tscm from naive precursors required the presence of the homeostatic cytokine interleukin-7 (IL-7). IL-7 promotes glucose uptake via overexpression of GLUT1 and upregulation of the glycolytic enzyme hexokinase 2. Even though metabolism depends on glucose uptake, the subsequent oxidation of pyruvate in the mitochondria was necessary for Tscm generation from naive precursors. In patients with T1D, high expression of GLUT1 was a hallmark of circulating Tscm, and targeting glucose uptake via GLUT1 using the selective inhibitor WZB117 resulted in inhibition of Tscm generation and expansion. Our results suggest that autoreactive Tscm are present in patients with T1D and can be selectively targeted by inhibition of glucose metabolism

A Study of Type 2 Mediated Immune Responses

Within tumors, immune responses strongly influence tumor development and stroma architecture, determining cancer progression. Tumor immune responses may be polarized towards a type 1-like “pro-inflammatory” or a type 2-like “alternative” phenotype, the latter mediated by type 2 cytokines (IL-4, IL-5, IL-9 and IL-13). Type 2 responses are generally thought to be associated with enhanced cancer growth. Whilst the effects of single type 2 cytokines in tumor progression have been extensively studied, the overall role of type 2 responses is far from thoroughly understood. In our study we utilised a unique quadruple IL-4/5/9/13 deficient mouse (T2KO), which features complete genetic depletion of type 2 responses. We assessed how the complete lack of type 2 cytokines affects both tumorigenesis and tumor progression. We showed that the complete lack of type 2 responses reduced tumor growth in a mouse model of transplantable breast carcinoma, correlating with improved T cell tumor infiltration and type 1 polarization. We further demonstrated that T cell depletion abolished the protective effects. Thus we formally demonstrated that type 2 responses promote tumor growth. Surprisingly, in carcinogen-driven tumor formation, lack of type 2 responses significantly increased tumor incidence. This was associated with a decreased protective fibrotic encapsulation of the carcinogen, matching pioneering studies on the protective effects of foreign body responses in carcinogenesis. The lack of carcinogen encapsulation in T2KO mice led to enhanced carcinogen spreading, thus suggesting that type 2 responses are protective against carcinogenesis. These findings further suggested a possible protective role against carcinogenesis of enhanced type 2 responses, such as in cases of allergy or asthma. To verify this, we examined two human patient cohorts, in Norway and Italy, and confirmed that, in men, pre-existing type 2 immune responses are significantly associated with reduced incidence of lung cancer. In summary, our findings suggest a protective role of type 2 responses from carcinogenesis, which may become detrimental in cancer progression. Our data also pose novel questions about the influence of immune responses on tumor formation, tumor growth and on tumor-associated fibrosis, occurring at different stages of the disease

Pharmacological Targeting of GLUT1 to Control Autoreactive T Cell Responses

An increasing body of evidence indicates that bio-energetic metabolism of T cells can be manipulated to control T cell responses. This potentially finds a field of application in the control of the T cell responses in autoimmune diseases, including in type 1 diabetes (T1D). Of the possible metabolic targets, Glut1 gained considerable interest because of its pivotal role in glucose uptake to fuel glycolysis in activated T cells, and the recent development of a novel class of small molecules that act as selective inhibitor of Glut1. We believe we can foresee a possible application of pharmacological Glut1 blockade approach to control autoreactive T cells that destroy insulin producing beta cells. However, Glut1 is expressed in a broad range of cells in the body and off-target and side effect are possible complications. Moreover, the duration of the treatment and the age of patients are critical aspects that need to be addressed to reduce toxicity. In this paper, we will review recent literature to determine whether it is possible to design a pharmacological Glut1 blocking strategy and how to apply this to autoimmunity in T1D

Manipulation of Glucose Availability to Boost Cancer Immunotherapies

The orchestration of T cell responses is intimately linked to the execution of metabolic processes, both in homeostasis and disease. In cancer tissues, metabolic alterations that characterize malignant transformation profoundly affect the composition of the immune microenvironment and the accomplishment of an effective anti-tumor response. The growing understanding of the metabolic regulation of immune cell function has shed light on the possibility to manipulate metabolic pathways as a strategy to improve T cell function in cancer. Among others, glucose metabolism through the glycolytic pathway is central in shaping T cell responses and emerges as an ideal target to improve cancer immunotherapy. However, metabolic manipulation requires a deep level of control over side-effects and development of biomarkers of response. Here, we summarize the metabolic control of T cell function and focus on the implications of metabolic manipulation for the design of immunotherapeutic strategies. Integrating our understanding of T cell function and metabolism will hopefully foster the forthcoming development of more effective immunotherapeutic strategies

T cell costimulation blockade blunts pressure overload-induced heart failure

Heart failure (HF) is a leading cause of mortality. Inflammation is implicated in HF, yet clinical trials targeting pro-inflammatory cytokines in HF were unsuccessful, possibly due to redundant functions of individual cytokines. Searching for better cardiac inflammation targets, here we link T cells with HF development in a mouse model of pathological cardiac hypertrophy and in human HF patients. T cell costimulation blockade, through FDA-approved rheumatoid arthritis drug abatacept, leads to highly significant delay in progression and decreased severity of cardiac dysfunction in the mouse HF model. The therapeutic effect occurs via inhibition of activation and cardiac infiltration of T cells and macrophages, leading to reduced cardiomyocyte death. Abatacept treatment also induces production of anti-inflammatory cytokine interleukin-10 (IL-10). IL-10-deficient mice are refractive to treatment, while protection could be rescued by transfer of IL 10-sufficient B cells. These results suggest that T cell costimulation blockade might be therapeutically exploited to treat HF