LGLs

LGLs, or large granular lymphocytes, are a subset of white blood cells characterized by their large size and cytoplasm filled with azurophilic granules. In healthy people, LGLs comprise a small portion of circulating lymphocytes. The term encompasses two main groups: natural killer (NK) cells, which are CD3-negative and typically express CD56 and/or CD16, and a subset of cytotoxic T lymphocytes (CTLs), which are CD3-positive and usually CD8-positive.

LGLs contribute to innate and adaptive immunity. NK cells recognize stressed or transformed cells and kill them by releasing perforin and granzymes. Cytotoxic T-LGLs recognize specific antigens presented by MHC class I and eliminate target cells through similar cytotoxic mechanisms and Fas-FasL–mediated pathways. Together, these cells help control viral infections and surveillance against malignant transformation.

In clinical practice, transient expansions of LGLs can accompany infections or autoimmune conditions. Persistent clonal expansions define disorders such as T-cell large granular lymphocytic leukemia (T-LGL leukemia) and chronic lymphoproliferative disorder of NK cells (CLPD-NK). Patients may have neutropenia, anemia, recurrent infections or splenomegaly. LGL leukemias are typically indolent but can cause cytopenias and autoimmune phenomena.

Diagnosis relies on a complete blood count showing elevated LGLs on smear, flow cytometry to characterize phenotype (NK cells: CD3-, CD56+/CD16+; T-LGLs: CD3+, CD8+), and sometimes molecular studies identifying clonal T-cell receptor rearrangements or STAT mutations.

Treatment focuses on managing cytopenias and symptoms; immunosuppressive therapy such as methotrexate, cyclophosphamide, or cyclosporine is commonly used. In selected cases, targeted therapies and clinical trials explore JAK/STAT inhibitors. Overall prognosis varies with disease subtype and severity.