Re-Programming Autoreactive T Cells Into T-Regulatory Type 1 Cells for the Treatment of Autoimmunity

Systemic delivery of peptide-major histocompatibility complex (pMHC) class II-based nanomedicines can re-program cognate autoantigen-experienced CD4+ T cells into disease-suppressing T-regulatory type 1 (TR1)-like cells. In turn, these TR1-like cells trigger the formation of complex regulatory cell networks that can effectively suppress organ-specific autoimmunity without impairing normal immunity. In this review, we summarize our current understanding of the transcriptional, phenotypic and functional make up of TR1-like cells as described in the literature. The true identity and direct precursors of these cells remain unclear, in particular whether TR1-like cells comprise a single terminally-differentiated lymphocyte population with distinct transcriptional and epigenetic features, or a collection of phenotypically different subsets sharing key regulatory properties. We propose that detailed transcriptional and epigenetic characterization of homogeneous pools of TR1-like cells will unravel this conundrum.

Type 2 immunity is maintained during cancer associated adipose tissue wasting

Cachexia is a systemic metabolic disorder characterized by loss of fat and muscle mass, which disproportionately impacts patients with gastrointestinal malignancies such as pancreatic cancer. While the immunologic shifts contributing to the development of other adipose tissue (AT) pathologies such as obesity have been well described, the immune microenvironment has not been studied in the context of cachexia. Here we assess the immune landscape of visceral AT (VAT) in the setting of pancreatic and colorectal cancers at the transcript, protein, and cellular levels. The cachexia inducing factor IL-6 is strongly elevated in the wasting VAT of cancer bearing mice, but the regulatory type 2 immune landscape which characterizes healthy VAT is maintained. Pathologic skewing toward Th1 and Th17 inflammation is absent. Similarly, the VAT of patients with colorectal cancer is characterized by a Th2 signature with abundant IL-33 and eotaxin-2, albeit also with high levels of IL-6. Our results suggest that wasting AT during the development of cachexia may not undergo drastic changes in immune composition like those seen in obese AT and provide a framework for further analyses of cancer associated cachexia.

EOMES and IL-10 regulate antitumor activity of T regulatory type 1 CD4+ T cells in chronic lymphocytic leukemia

The transcription factor eomesodermin (EOMES) promotes interleukin (IL)-10 expression in CD4+ T cells, which has been linked to immunosuppressive and cytotoxic activities. We detected cytotoxic, programmed cell death protein-1 (PD-1) and EOMES co-expressing CD4+ T cells in lymph nodes (LNs) of patients with chronic lymphocytic leukemia (CLL) or diffuse large B-cell lymphoma. Transcriptome and flow cytometry analyses revealed that EOMES does not only drive IL-10 expression, but rather controls a unique transcriptional signature in CD4+ T cells, that is enriched in genes typical for T regulatory type 1 (TR1) cells. The TR1 cell identity of these CD4+ T cells was supported by their expression of interferon gamma and IL-10, as well as inhibitory receptors including PD-1. TR1 cells with cytotoxic capacity accumulate also in Eµ-TCL1 mice that develop CLL-like disease. Whereas wild-type CD4+ T cells control TCL1 leukemia development after adoptive transfer in leukopenic Rag2−/− mice, EOMES-deficient CD4+ T cells failed to do so. We further show that TR1 cell-mediated control of TCL1 leukemia requires IL-10 receptor (IL-10R) signaling, as Il10rb-deficient CD4+ T cells showed impaired antileukemia activity. Altogether, our data demonstrate that EOMES is indispensable for the development of IL-10-expressing, cytotoxic TR1 cells, which accumulate in LNs of CLL patients and control TCL1 leukemia in mice in an IL-10R-dependent manner.

837 Interleukin-10 drives the development of T regulatory type 1 (Tr1) cells and is a target for immunotherapy

BackgroundIn recent years, immunotherapy has become a common tool of cancer treatment. In order to define therapeutic targets, it is necessary to understand mechanisms of tumor-induced immunosuppression. In malignant B-cell lymphoma, the effects of the anti-inflammatory cytokine interleukin-10 (IL-10) remain poorly understood.MethodsTo investigate the role of IL-10 in a tumor microenvironment, we used λ-MYC-transgenic mice that spontaneously develop B-cell lymphoma. The experiments were performed either in vivo or in vitro and the cell samples were then analyzed by flow cytometry.ResultsIn MYC tumors, CD4+Foxp3- effector T cells maintained the expression of interferon-γ (IFN-γ), yet became exhausted. Within this population we found a cell fraction of unknown origin coexpressing IFN-γ and IL-10 that increased during disease progression. These cells turned out to be T regulatory type 1 (Tr1) cells, which are known to be immunosuppressive. When exposing homogeneous IFN-γ-producing T helper type 1 (Th1) cells to a MYC tumor milieu in vitro, part of these cells started to express both, IFN-γ and IL-10, and showed an increased level of programmed cell death protein 1 (PD-1). Notably, these changes diminished when an IL-10 neutralizing monoclonal antibody (mAb) was added to the coculture, indicating that IL-10 is necessary for the Tr1 development and is involved in the upregulation of PD-1. In line with these results, we treated λ-MYC mice with anti-IL-10 mAb. This therapy not only led to significantly prolonged survival but also decreased expression of PD-1 on effector T cells and increased proliferation of cytotoxic T cells.ConclusionsIn summary, these results showed the importance of IL-10 for the tumor immune escape in lymphoma. IL-10 induced a conversion from Th1 to Tr1 cells and elevated levels of PD-1. Both effects were diminished after IL-10 ablation. Thus, targeting IL-10 might be a promising new approach of immunotherapy.Ethics ApprovalAll animal studies were approved by Regierung von Oberbayern, approval number 55.2-1-54.