{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n CARMIL2 is a multidomain cytoskeletal regulator that plays a critical role in the adaptive immune response. Although originally linked to actin-uncapping, its principal function in T cells is to serve as a scaffold that couples the co‐stimulatory receptor CD28 to downstream effectors—including CARD11 and components of the NF‐κB pathway—to enable full T‐cell activation (1). Intriguingly, this scaffolding role is essential for CD28-mediated co-stimulation in both human and murine T cells, while its presumed actin regulatory (uncapping) activity appears to be dispensable in that context (1). In addition, in migrating cells CARMIL2 is uniquely distributed: it localizes both to membranes and to vimentin intermediate filaments and utilizes a conserved membrane-binding domain to support cell polarity, lamellipodial assembly, and macropinocytosis. This distinct spatial organization enables CARMIL2 to integrate cytoskeletal dynamics with membrane-associated signaling (2). Moreover, loss-of-function mutations in CARMIL2 disrupt CD28 co-signaling and T-cell activation, resulting in a combined immunodeficiency characterized by impaired regulatory and memory T-cell formation. This immunological defect manifests clinically with recurrent infections, skin disorders, and gastrointestinal inflammation, as documented in patients with early-onset bowel disease and related immune dysregulatory conditions (3,4,5). Together, these findings underscore CARMIL2 as a key integrator of cytoskeletal architecture and immune receptor signaling that is essential for proper T-cell co-stimulation and immune homeostasis.\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n (1)"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "; (2)"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "; (3)"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "; (4)"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "; (5)."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Romain Roncagalli, Margot Cucchetti, Nicolas Jarmuzynski, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The scaffolding function of the RLTPR protein explains its essential role for CD28 co-stimulation in mouse and human T cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Exp Med (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1084/jem.20160579"}], "href": "https://doi.org/10.1084/jem.20160579"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27647348"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27647348"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "M Hunter Lanier, Patrick McConnell, John A Cooper "}, {"type": "b", "children": [{"type": "t", "text": "Cell Migration and Invadopodia Formation Require a Membrane-binding Domain of CARMIL2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M115.676882"}], "href": "https://doi.org/10.1074/jbc.M115.676882"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26578515"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26578515"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Anas M Alazami, Maryam Al-Helale, Safa Alhissi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Novel CARMIL2 Mutations in Patients with Variable Clinical Dermatitis, Infections, and Combined Immunodeficiency."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Front Immunol (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3389/fimmu.2018.00203"}], "href": "https://doi.org/10.3389/fimmu.2018.00203"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29479355"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29479355"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Alina Kurolap, Orly Eshach Adiv, Liza Konnikova, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A Unique Presentation of Infantile-Onset Colitis and Eosinophilic Disease without Recurrent Infections Resulting from a Novel Homozygous CARMIL2 Variant."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Immunol (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s10875-019-00631-6"}], "href": "https://doi.org/10.1007/s10875-019-00631-6"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31079270"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31079270"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Luca Bosa, Vritika Batura, Davide Colavito, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Novel CARMIL2 loss-of-function variants are associated with pediatric inflammatory bowel disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Rep (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41598-021-85399-9"}], "href": "https://doi.org/10.1038/s41598-021-85399-9"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33723309"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33723309"}]}]}]}