Ming O. Li

TGF-β: A Master of All T Cell Trades

A functional adaptive immune system depends on a diverse and self-tolerant population of T lymphocytes that are generated in the thymus and maintained in the peripheral lymphoid organs. Recent studies have defined the cytokine transforming growth factor-beta (TGF-beta) as a critical regulator of thymic T cell development as well as a crucial player in peripheral T cell homeostasis, tolerance to self antigens, and T cell differentiation during the immune response. The unique mechanism of TGF-beta activation and the plasticity of TGF-beta signaling create a stage for TGF-beta to integrate signals from multiple cell types and environmental cues to regulate T cells.

The cellular and molecular origin of tumor-associated macrophages

Long recognized as an evolutionarily ancient cell type involved in tissue homeostasis and immune defense against pathogens, macrophages are being rediscovered as regulators of several diseases, including cancer. Here we show that in mice, mammary tumor growth induces the accumulation of tumor-associated macrophages (TAMs) that are phenotypically and functionally distinct from mammary tissue macrophages (MTMs). TAMs express the adhesion molecule Vcam1 and proliferate upon their differentiation from inflammatory monocytes, but do not exhibit an “alternatively activated” phenotype. TAM terminal differentiation depends on the transcriptional regulator of Notch signaling, RBPJ; and TAM, but not MTM, depletion restores tumor-infiltrating cytotoxic T cell responses and suppresses tumor growth. These findings reveal the ontogeny of TAMs and a discrete tumor-elicited inflammatory response, which may provide new opportunities for cancer immunotherapy. Origins of tumor macrophages To help the immune system fight cancer, it is important to understand the origins and functions of immune cells in tumors and the surrounding tissues. One type of immune cells, macrophages, is present both in tumors and in nearby noncancerous tissue, but the relationship between these two cell populations is unclear. Franklin et al. found that tumor-associated macrophages in mouse mammaries differed in form, function, and origin from macrophages found in nearby noncancerous mammary tissue. Moreover, when they removed macrophages from the tumors but not the other mammary tissue, tumors shrank and cytotoxic T cells—another kind of immune cell that kills tumor cells—infiltrated the tumors. Tumor-associated macrophages may thus be an important therapeutic target. Science, this issue p. 921. The origins of tumor-associated macrophages in a mouse mammary tumor model are revealed. [Also see Perspective by Perdiguero and Geissmann]

Contextual Regulation of Inflammation : A Duet by Transforming Growth Factor-β and Interleukin-10

Transforming growth factor-beta (TGF-beta) and interleukin-10 (IL-10) are regulatory cytokines with pleiotropic roles in the immune system. The prominent function of TGF-beta is to maintain T cell tolerance to self or innocuous environmental antigens via its direct effects on the differentiation and homeostasis of effector and regulatory T cells. A critical route for the regulation of T cells by TGF-beta is via activation of a T cell-produced latent form of TGF-beta1 by dendritic cell-expressed avbeta8 integrin. IL-10 operates primarily as a feedback inhibitor of exuberant T cell responses to microbial antigens. T cells are also the principal producers of IL-10, the expression of which is regulated by IL-27, IL-6, and TGF-beta. The collective activity of TGF-beta and IL-10 ensures a controlled inflammatory response specifically targeting pathogens without evoking excessive immunopathology to self-tissues.

Bone Marrow Mesenchymal Stem and Progenitor Cells Induce Monocyte Emigration in Response to Circulating Toll-like Receptor Ligands

Inflammatory (Ly6C(hi) CCR2+) monocytes provide defense against infections but also contribute to autoimmune diseases and atherosclerosis. Monocytes originate from bone marrow and their entry into the bloodstream requires stimulation of CCR2 chemokine receptor by monocyte chemotactic protein-1 (MCP1). How monocyte emigration from bone marrow is triggered by remote infections remains unclear. We demonstrated that low concentrations of Toll-like receptor (TLR) ligands in the bloodstream drive CCR2-dependent emigration of monocytes from bone marrow. Bone marrow mesenchymal stem cells (MSCs) and their progeny, including CXC chemokine ligand (CXCL)12-abundant reticular (CAR) cells, rapidly expressed MCP1 in response to circulating TLR ligands or bacterial infection and induced monocyte trafficking into the bloodstream. Targeted deletion of MCP1 from MSCs impaired monocyte emigration from bone marrow. Our findings suggest that bone marrow MSCs and CAR cells respond to circulating microbial molecules and regulate bloodstream monocyte frequencies by secreting MCP1 in proximity to bone marrow vascular sinuses.

Novel Foxo1-dependent transcriptional programs control T reg cell function

Regulatory T (Treg) cells, characterized by expression of the transcription factor forkhead box P3 (Foxp3), maintain immune homeostasis by suppressing self-destructive immune responses. Foxp3 operates as a late-acting differentiation factor controlling Treg cell homeostasis and function, whereas the early Treg-cell-lineage commitment is regulated by the Akt kinase and the forkhead box O (Foxo) family of transcription factors. However, whether Foxo proteins act beyond the Treg-cell-commitment stage to control Treg cell homeostasis and function remains largely unexplored. Here we show that Foxo1 is a pivotal regulator of Treg cell function. Treg cells express high amounts of Foxo1 and display reduced T-cell-receptor-induced Akt activation, Foxo1 phosphorylation and Foxo1 nuclear exclusion. Mice with Treg-cell-specific deletion of Foxo1 develop a fatal inflammatory disorder similar in severity to that seen in Foxp3-deficient mice, but without the loss of Treg cells. Genome-wide analysis of Foxo1 binding sites reveals ∼300 Foxo1-bound target genes, including the pro-inflammatory cytokine Ifng, that do not seem to be directly regulated by Foxp3. These findings show that the evolutionarily ancient Akt–Foxo1 signalling module controls a novel genetic program indispensable for Treg cell function.

An Essential Role of the Forkhead-Box Transcription Factor Foxo1 in Control of T Cell Homeostasis and Tolerance

Members of the Forkhead box O (Foxo) family of transcription factors are key regulators of cellular responses, but their function in the immune system remains incompletely understood. Here we showed that T cell-specific deletion of Foxo1 gene in mice led to spontaneous T cell activation, effector T cell differentiation, autoantibody production, and the induction of inflammatory bowel disease in a transfer model. In addition, Foxo1 was critical for the maintenance of naive T cells in the peripheral lymphoid organs. Transcriptome analyses of T cells identified Foxo1-regulated genes encoding, among others, cell-surface molecules, signaling proteins, and nuclear factors that control gene expression. Functional studies validated interleukin-7 receptor-alpha as a Foxo1 target gene essential for Foxo1 maintenance of naive T cells. These findings reveal crucial functions of Foxo1-dependent transcription in control of T cell homeostasis and tolerance.

Transforming Growth Factor-β Signaling Curbs Thymic Negative Selection Promoting Regulatory T Cell Development

Thymus-derived naturally occurring regulatory T (nTreg) cells are necessary for immunological self-tolerance. nTreg cell development is instructed by the T cell receptor and can be induced by agonist antigens that trigger T cell-negative selection. How T cell deletion is regulated so that nTreg cells are generated is unclear. Here we showed that transforming growth factor-beta (TGF-beta) signaling protected nTreg cells and antigen-stimulated conventional T cells from apoptosis. Enhanced apoptosis of TGF-beta receptor-deficient nTreg cells was associated with high expression of proapoptotic proteins Bim, Bax, and Bak and low expression of the antiapoptotic protein Bcl-2. Ablation of Bim in mice corrected the Treg cell development and homeostasis defects. Our results suggest that nTreg cell commitment is independent of TGF-beta signaling. Instead, TGF-beta promotes nTreg cell survival by antagonizing T cell negative selection. These findings reveal a critical function for TGF-beta in control of autoreactive T cell fates with important implications for understanding T cell self-tolerance mechanisms.

Signaling through C5a receptor and C3a receptor diminishes function of murine natural regulatory T cells

Blockade of C3aR/C5aR signaling in nT reg cells augments in vitro and in vivo suppression, abrogates autoimmune colitis, and prolongs allogeneic skin graft survival.

Aerobic glycolysis promotes T helper 1 cell differentiation through an epigenetic mechanism

Metabolic support for T cell functions For immunological T cells, responding to infections is energetically demanding. T cells rewire their metabolism so that they rely more heavily on aerobic glycolysis. This helps them to support important effector functions such as secreting the cytokine interferon γ (IFNγ). Peng et al. now provide insight into how aerobic glycolysis promotes T cell effector function. Activated T cells express the aerobic glycolysis–supporting enzyme lactate dehydrogenase A (LDHA), allowing these cells to maintain high amounts of acetyl–coenzyme A, which in turn promotes histone acetylation and transcription of cytokines such as IFNγ. Engineered mice whose T cells lacked LDHA were protected from IFNγ-dependent pathologies that often characterize autoinflammatory diseases. Science, this issue p. 481 Immunological T cell effector functions are promoted by metabolic activity–modifying levels of histone acetylation. Aerobic glycolysis (the Warburg effect) is a metabolic hallmark of activated T cells and has been implicated in augmenting effector T cell responses, including expression of the proinflammatory cytokine interferon-γ (IFN-γ), via 3′ untranslated region (3′UTR)–mediated mechanisms. Here, we show that lactate dehydrogenase A (LDHA) is induced in activated T cells to support aerobic glycolysis but promotes IFN-γ expression independently of its 3′UTR. Instead, LDHA maintains high concentrations of acetyl–coenzyme A to enhance histone acetylation and transcription of Ifng. Ablation of LDHA in T cells protects mice from immunopathology triggered by excessive IFN-γ expression or deficiency of regulatory T cells. These findings reveal an epigenetic mechanism by which aerobic glycolysis promotes effector T cell differentiation and suggest that LDHA may be targeted therapeutically in autoinflammatory diseases.

T cell receptor signalling in the control of regulatory T cell differentiation and function.

Regulatory T cells (TReg cells), a specialized T cell lineage, have a pivotal function in the control of self tolerance and inflammatory responses. Recent studies have revealed a discrete mode of T cell receptor (TCR) signalling that regulates TReg cell differentiation, maintenance and function and that affects gene expression, metabolism, cell adhesion and migration of these cells. Here, we discuss the emerging understanding of TCR-guided differentiation of TReg cells in the context of their function in health and disease.