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T lymphocyte populations within the lamina propria
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Thomas T. MacDonald, Antonio Di Sabatino
T-cell subset plasticity is not, however, limited to Treg cells. The transition of CD4+ T cells of one effector subset to progeny with features of a distinct effector subset has been increasingly reported. This has been most clearly demonstrated for TH17 cells, which can give rise to TH1-like cells contingent on the hierarchy of cytokine signals received following TH17 cell differentiation. In particular, TH17 cells exposed to the TH1-polarizing cytokine IL-12 extinguish expression of genes that encode IL-17 cytokines in favor of IFN-γ. The transition of TH17 cells into IFN-γ-producing TH1 cells is dependent on STAT4 signaling and induction of the TH1 lineage transcription factor, T-bet. Similar to the transition of Treg cells to T effector cells, TH17–TH1 transitions appear to be unidirectional. That is, TH17 cells can transition to TH1 cells, but TH1 cells do not transition to TH17 cells. In intestinal inflammation in mice, the transition of TH17 cells into TH1-type cells is associated with the development of colitis, suggesting that the mix of TH17 and TH1 cells typically found in the intestinal lamina propria, both at homeostasis and in IBD, might be due to diversion of some TH17 precursors locally in the intestines (Figure 7.3). An important contribution to the fate of Th17 cells is the observation using fate mapping that in the gut Th17 cells can become ex-Th17 cells and begin to make IL-10, similar to Treg-1 cells. The relevance of this to gut inflammation is that IL-10R mutations in children lead to early onset gut inflammation, and the source of IL-10 may be exTh17 cells.
Influencing tumor-associated macrophages in malignant melanoma with monoclonal antibodies
Published in OncoImmunology, 2022
Rebecca Adams, Gabriel Osborn, Bipashna Mukhia, Roman Laddach, Zena Willsmore, Alicia Chenoweth, Jenny L C Geh, Alastair D MacKenzie Ross, Ciaran Healy, Linda Barber, Sophia Tsoka, Victoria Sanz-Moreno, Katie E Lacy, Sophia N Karagiannis
Melanoma-associated macrophages can derive either from embryonic-derived tissue resident macrophages (Res-TAMs), recruited and maintained by colony-stimulating factor-1 (CSF-1) binding its receptor CSF1R,25 or through the recruitment of circulating monocytes via the CCL2/CCR2 chemokine pathway, which can differentiate into monocyte-derived macrophages (mo-TAMs).26–28 The exact contributions of each origin pool are still being explored, with a paucity of information on how macrophage ontogeny affects TAM function within melanoma. Much knowledge of ontogeny derives from mouse studies, due to the inability to undertake fate-mapping studies in humans. Alongside this, genetic similarities and a lack of markers that can help distinguish tissue-resident from monocyte-derived macrophages render further exploration into this area quite challenging.29 It appears that tissue resident macrophages are the first to be influenced by factors secreted from tumors. However, in the cancer types studied so far, the contribution of Res-TAMs and mo-TAMs appears organ specific:29–31 in pancreatic cancer models, Res-TAMs appeared to promote tumor growth; in human glioma samples mo-TAMs correlate with tumor grade; and in mouse models of lung cancer, macrophages of both origins appear to contribute to tumor growth. No such comparative studies of how macrophage origin can affect function have been carried out in melanoma.
Retinal Pericytes: Characterization of Vascular Development-Dependent Induction Time Points in an Inducible NG2 Reporter Mouse Model
Published in Current Eye Research, 2018
Daniela Bruckner, Alexandra Kaser-Eichberger, Barbara Bogner, Christian Runge, Falk Schrödl, Clemens Strohmaier, Maria Elena Silva, Pia Zaunmair, Sebastien Couillard-Despres, Ludwig Aigner, Francisco J. Rivera, Herbert A. Reitsamer, Andrea Trost
Pericytes (PCs) are specialized cells which are located abluminal of endothelial cells (ECs) on capillaries.1 PCs are in direct contact with ECs, communicate via paracrine growth factor signaling, and share a common basement membrane.2 PCs play an important role in vascular development as well as in stabilization, maturation, and remodeling of microvessels, making them indispensable for tissue homeostasis.3 Further, PCs are part of the neurovascular unit and therefore an essential constituent of the blood-brain barrier/blood-retina barrier (BBB/BRB), maintaining a highly regulated, selective barrier function.4–7 Due to the ability of PCs to participate and differentiate in physiological and pathological situations, their gene and protein expression profile is diverse and adapted to their current differentiation state, which makes the identification of PCs challenging. However, in general, PCs located on microvessels show a spherical shaped soma with a prominent nucleus and processes which extend longitudinal on and around the vessel wall, covering several ECs.8,9 As a part of the central nervous system (CNS), the retina exhibits a high PC density with a PC to EC ratio of about 1:1 to 1:3, which is constant in healthy conditions.8 In general, abnormalities in PC function or an unbalanced PC coverage of the vessels are directly associated with various pathologies. These include, e.g., the BBB breakdown in multiple sclerosis, Parkinson’s and Alzheimer’s disease, or the PC dropout and BRB breakdown in DR.10–12 Therefore, PCs are promising future targets to develop new therapeutic strategies in order to prevent PC loss and drop out. As no unique PC marker is available and since PCs alter their expression profile under various conditions, a PC fate mapping mouse model would represent an invaluable tool to understand their biology, with the aim to develop new therapeutic strategies.
Characterization of the Two Inducible Cre Recombinase-Based Mouse Models NG2-CreER™ and PDGFRb-P2A-CreERT2 for Pericyte Labeling in the Retina
Published in Current Eye Research, 2022
Daniela Mayr, Julia Preishuber-Pflügl, Andreas Koller, Susanne M. Brunner, Christian Runge, Anja-Maria Ladek, Francisco J. Rivera, Herbert A. Reitsamer, Andrea Trost
Pericytes (PCs) are located abluminal of microvessels and share a common basement membrane with endothelial cells (ECs). ECs and PCs are in physical contact and communicate with each other by paracrine signaling, using factors like platelet-derived growth factor B (PDGF-B), vascular endothelial growth factor (VEGF), transforming growth factor-beta (TGFb), and angiopoietins (Ang-1 and Ang-2).1 PCs function as regulators of angiogenesis, in-vessel stabilization, maturation, and remodeling of microvessels and are therefore indispensable in tissue homeostasis. As PCs express contractile proteins and have the potential to contract, they participate in the regulation of microvascular blood flow and neurovascular coupling.2–4 Moreover, PCs display mesenchymal stem cell character, as they can differentiate into other cell types, such as adipocytes, osteoblasts, chondrocytes, and phagocytes in vitro.5,6 In addition to their plasticity, PCs are also reported to play a critical role in wound healing and tissue repair7 and are therefore important targets for regenerative approaches. Furthermore, they contribute to the formation of the blood-brain- and the blood-retina-barrier.8 Reduced PC coverage or abnormalities in PC function are associated with various pathologies, including multiple sclerosis, Parkinson’s and Alzheimer’s disease,8,9 or diabetic retinopathy.10 Retinal vessels show the highest PC density among the human body.11 However, the fate of PCs in the retina during ocular diseases is still not well-understood and needs to be further investigated. As no unique PC marker is available and since PCs alter their expression profile under various conditions, a PC fate mapping mouse model represents a valuable tool to study their biology, function, and behavior under physiological and pathological conditions. Gene expression and morphology of PCs differ depending on their localization and differentiation state in the tissue. In general, they have a round-shaped soma with a prominent nucleus and few processes, which extend longitudinally on and around the capillary.12,13 Detecting PCs are challenging due to their diverse tissue-dependent appearances.12,14 Nevertheless, to identify and characterize PCs several markers have been established, including desmin, vimentin, neural/glial antigen 2 (NG2; also named chondroitin sulfate proteoglycan 4), platelet-derived growth factor receptor beta (PDGFRb), aminopeptidase N (CD13), potassium inwardly-rectifying channel, subfamily J, member (Kir6.1), and regulator of G protein signaling 5 (RGS5).2,12,15–19 NG2 is a widely used marker for oligodendrocyte precursor cells in the central nervous system, as well as chondroblasts and aortic smooth muscle cells, PCs, and vSMCs.16,20 Since the retina is devoid of myelinated structures and cells of the oligodendroglial lineage, NG2 only labels PCs and vSMCs.