{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n CXCR3 is a pivotal chemokine receptor that orchestrates immune cell trafficking and function in a variety of contexts. It is expressed on multiple lymphocyte subsets – notably on T helper 1 (Th1) cells and on a subset of pathogenic Th17 cells that co‐produce interferon‑γ, where its engagement by the ligands CXCL9, CXCL10, and CXCL11 helps guide these cells to sites of inflammation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In addition, CXCR3 plays an essential role in innate responses; for example, in mice, natural killer (NK) cells are rapidly recruited in a CXCR3‑dependent manner to lymph nodes in response to dendritic cell activation, which in turn facilitates early interferon‑γ production and Th1 polarization."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " Moreover, CXCR3 is up‑regulated on regulatory T cells (Tregs) in an interferon‑γ– and T‑bet–dependent fashion, thereby enabling these cells to home to areas of Th1‑mediated inflammation where they can temper immune responses."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the tumor and infection settings, the CXCR3 axis is critical for directing effector CD8⁺ T cells toward sites that are rich in CXCR3 ligands – a function that enhances their migratory speed and cytolytic activity, thereby improving immunosurveillance and responses against both tumors and pathogens."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " In parallel, alternative splicing generates a CXCR3‑B variant that is preferentially expressed on endothelial cells; rather than promoting migration, CXCR3‑B mediates angiostatic signals and can induce apoptosis, suggesting a counterregulatory mechanism in vascular remodeling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Finally, CXCR3 is also implicated in non‐classical settings. In celiac disease, for instance, gliadin from wheat binds to CXCR3 on intestinal epithelial cells, triggering a MyD88‑dependent zonulin release that increases intestinal permeability and may contribute to disease pathogenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Together, these studies underscore the multifaceted role of CXCR3 – from mediating the directed migration of effector and regulatory lymphocytes in inflammatory, infectious, and neoplastic conditions to modulating angiostasis and barrier function – highlighting its potential as a therapeutic target in a diverse array of immune‐driven pathologies.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Eva V Acosta-Rodriguez, Laura Rivino, Jens Geginat, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Immunol (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ni1467"}], "href": "https://doi.org/10.1038/ni1467"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17486092"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17486092"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Radha Ramesh, Lina Kozhaya, Kelly McKevitt, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Pro-inflammatory human Th17 cells selectively express P-glycoprotein and are refractory to glucocorticoids."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Exp Med (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1084/jem.20130301"}], "href": "https://doi.org/10.1084/jem.20130301"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24395888"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24395888"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Alfonso Martín-Fontecha, Lindy L Thomsen, Sara Brett, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Induced recruitment of NK cells to lymph nodes provides IFN-gamma for T(H)1 priming."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Immunol (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ni1138"}], "href": "https://doi.org/10.1038/ni1138"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15531883"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15531883"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Meghan A Koch, Glady's Tucker-Heard, Nikole R Perdue, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Immunol (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ni.1731"}], "href": "https://doi.org/10.1038/ni.1731"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19412181"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19412181"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Stephanie A McClymont, Amy L Putnam, Michael R Lee, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Plasticity of human regulatory T cells in healthy subjects and patients with type 1 diabetes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.1003099"}], "href": "https://doi.org/10.4049/jimmunol.1003099"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21368230"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21368230"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Mingli Liu, Shanchun Guo, Jacqueline M Hibbert, et al. "}, {"type": "b", "children": [{"type": "t", "text": "CXCL10/IP-10 in infectious diseases pathogenesis and potential therapeutic implications."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cytokine Growth Factor Rev (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cytogfr.2011.06.001"}], "href": "https://doi.org/10.1016/j.cytogfr.2011.06.001"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21802343"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21802343"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Tajie H Harris, Edward J Banigan, David A Christian, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Generalized Lévy walks and the role of chemokines in migration of effector CD8+ T cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nature (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nature11098"}], "href": "https://doi.org/10.1038/nature11098"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22722867"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22722867"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Laura Lasagni, Michela Francalanci, Francesco Annunziato, et al. "}, {"type": "b", "children": [{"type": "t", "text": "An alternatively spliced variant of CXCR3 mediates the inhibition of endothelial cell growth induced by IP-10, Mig, and I-TAC, and acts as functional receptor for platelet factor 4."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Exp Med (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1084/jem.20021897"}], "href": "https://doi.org/10.1084/jem.20021897"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12782716"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12782716"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Yvonne Junker, Sebastian Zeissig, Seong-Jun Kim, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Wheat amylase trypsin inhibitors drive intestinal inflammation via activation of toll-like receptor 4."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Exp Med (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1084/jem.20102660"}], "href": "https://doi.org/10.1084/jem.20102660"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23209313"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23209313"}]}]}]}