Insights into the heterogeneity of iNKT cells: tissue-resident and circulating subsets shaped by local microenvironmental cues.

Invariant natural killer T (iNKT) cells are a distinct subpopulation of innate-like T lymphocytes. They are characterized by semi-invariant T cell receptors (TCRs) that recognize both self and foreign lipid antigens presented by CD1d, a non-polymorphic MHC class I-like molecule. iNKT cells play a critical role in stimulating innate and adaptive immune responses, providing an effective defense against infections and cancers, while also contributing to chronic inflammation. The functions of iNKT cells are specific to their location, ranging from lymphoid to non-lymphoid tissues, such as the thymus, lung, liver, intestine, and adipose tissue. This review aims to provide insights into the heterogeneity of development and function in iNKT cells. First, we will review the expression of master transcription factors that define subsets of iNKT cells and their production of effector molecules such as cytokines and granzymes. In this article, we describe the gene expression profiles contributing to the kinetics, distribution, and cytotoxicity of iNKT cells across different tissue types. We also review the impact of cytokine production in distinct immune microenvironments on iNKT cell heterogeneity, highlighting a recently identified circulating iNKT cell subset. Additionally, we explore the potential of exploiting iNKT cell heterogeneity to create potent immunotherapies for human cancers in the future.

CD45 alleviates airway inflammation and lung fibrosis by limiting expansion and activation of ILC2s.

Group 2 innate lymphoid cells (ILC2s) are critical for the immune response against parasite infection and tissue homeostasis and involved in the pathogenesis of allergy and inflammatory diseases. Although multiple molecules positively regulating ILC2 development and activation have been extensively investigated, the factors limiting their population size and response remain poorly studied. Here, we found that CD45, a membrane-bound tyrosine phosphatase essential for T cell development, negatively regulated ILC2s in a cell-intrinsic manner. ILC2s in CD45-deficient mice exhibited enhanced proliferation and maturation in the bone marrow and hyperactivated phenotypes in the lung with high glycolytic capacity. Furthermore, CD45 signaling suppressed the type 2 inflammatory response by lung ILC2s and alleviated airway inflammation and pulmonary fibrosis. Finally, the interaction with galectin-9 influenced CD45 signaling in ILC2s. These results demonstrate that CD45 is a cell-intrinsic negative regulator of ILC2s and prevents lung inflammation and fibrosis via ILC2s.