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It presents with cytopenias that are not explained by the typically low leukemic burden. Notably, T-LGLL is frequently accompanied by autoimmune disorders, particularly rheumatoid arthritis (RA). As clonal T-cell expansions are also increasingly identified in autoimmune-driven conditions, better models of T-LGLL\u2019s pathogenesis as a spectrum of (auto)antigen-driven oligoclonal hierarchies towards overt leukemic escape with associated immune dysregulations would provide details to a valuable prototype for determinants of T-cell fitness and transformation as well as T-cell instructed dysfunctions of other immune cells. Such insights would advance our concepts of cancer biology and immunology. Common molecular links between T-LGLL and autoimmune diseases include activation of JAK\/STAT signaling, proinflammatory cytokine environments, and antigen-driven immune responses. Current murine models address these mechanisms rather individually: JAK\/STAT based systems replicate pathway activation, cytokine-driven models simulate inflammatory conditions, and RA models often mimic antigen stimulation. However, none of these fully captures the duality of clonal T-cell expansion and the complex immune dysregulations, inherent to T-LGLL. This review examines criteria for autochthonous in-vivo T-LGLL models and evaluates existing systems, identifying their strengths, limitations, and specific representations of clinico-pathologic aspects of LGLL. Prominent transgenic models, for example, not only manipulate the T-cell compartment but also indiscriminately alter the tumor microenvironment, impeding research on the specific role of elements of the LGLL micromilieu. We propose strategies to overcome such insufficiencies of present models. Overall, our critical appraisal emphasizes the need for novel comprehensive models that more faithfully integrate the key features of T-LGLL or for models that, by featuring specific pathogenetic aspects of the disease, would supplement existing incomplete systems. We expect such new model systems to aid in better understanding the cancer-immunity interface and in assessing novel therapeutic approaches for T-LGLL.<\/jats:p>","DOI":"10.1038\/s41375-025-02553-2","type":"journal-article","created":{"date-parts":[[2025,3,7]],"date-time":"2025-03-07T17:15:39Z","timestamp":1741367739000},"page":"792-804","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Models for T-large granular lymphocytic leukemia: how to mimic the cellular interplays in malignant autoimmunity"],"prefix":"10.1038","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-8369-8115","authenticated-orcid":false,"given":"Hanna","family":"Klepzig","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marco","family":"Herling","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natali","family":"Pflug","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0854-7815","authenticated-orcid":false,"given":"Till","family":"Braun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,3,7]]},"reference":[{"key":"2553_CR1","doi-asserted-by":"crossref","unstructured":"Moignet A, Lamy T. 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