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Bhandoola and colleagues describe the existence of two pathways of NK cell development that generate functionally distinct NK cell subsets in mice, and which may be conserved in humans.

The thymus produces T cells, and an improved understanding of thymus biology is likely to have therapeutic potential. Here we summarize the 2025 ThymUS conference, focusing on fundamental insights and translational potential.

The cellular and molecular events that drive early innate lymphoid cell (ILC) development remain poorly understood. Bhandoola and colleagues used a reporter mouse to identify a new subset of early ILC progenitors (EILPs) that express high amounts of TCF-1.

Stemness is crucial for the maintenance of long-term T cell memory. Gattinoni and colleagues demonstrate that the transcription factor c-Myb is essential for the establishment of a stemness program in the CD8⁺ T cell memory compartment.

Bhandoola and colleagues show that the transcription factor TCF-1 restrains the dendritic cell lineage potential in innate lymphoid cell progenitors.

Although T cells are derived from haematopoietic stem cells in the bone marrow, T-cell development occurs in the thymus. This Review describes recent data indicating that several cell populations in the bone marrow are able to populate the thymus and generate T cells.

Hematopoietic deficiency in the Notch target Hes1 results in severe defects in the T cell lineage. Bhandoola and colleagues show that Hes1 constrains myeloid gene-expression programs in T cell progenitors.

Hematopoietic stem cells (HSCs) differentiate into multiple lineages, with such capacity impacted by aging. Here the authors identify Kit^lo HSCs as a functionally distinct population that exhibits distinct lymphoid-primed chromatin landscapes, which drive enhanced lymphoid reconstitution capacity, and is altered in aged hosts.

We demonstrate the role of the ligand-gated purinergic ion channel P2RX4 in maintaining mouse plasma cells in their bone marrow niche.

Thymic epithelial cells (TEC) are essential for the maturation of functional T cells, while thymus size is proportional to the overall output efficiency. Here the authors show, using transcriptome analyses, that mouse fetal TEC maintain a Myc-dependent genetic program to ensure a rapid increase in thymus size, and thereby expedited T cell generation.

Several non-haematopoietic-cell-derived cytokines, including interleukin (IL)25, have been implicated in inducing T helper 2 (T_H2) cell-dependent inflammation, but their precise role has been unclear. Here, IL25 is shown to promote the accumulation of multipotent progenitor cells in gut-associated lymphoid tissue. These cells can give rise to macrophage or granulocyte lineages that promote the differentiation of T_H2 cells and contribute to protective immunity against helminth infections.

ThPOK is necessary for the differentiation of CD4⁺ helper T cells. Three new studies indicate that, unexpectedly, ThPOK is required only after initial specification to the CD4⁺ lineage.

An algorithm developed with a systems-biology approach reconstructs some of the key regulatory events known to drive the development of cells of the mouse immune system and makes many other novel predictions for testing.

One of two papers that show there is a single type of progenitor within the adult thymus that possesses both T and myeloid potential. It is shown that T cells are produced by an early population in the thymus that has lost the ability to produce B cells, but can still produce macrophages as well as cells with T, NK and dendritic cell potential. These papers therefore argue against the classical dichotomy model in which T cells are derived from common lymphoid progenitors, and support a model for adult hematopoeisis where the progenitor cell at the branch point of the T and B cell lineages retains macrophage potential.

T cell progenitors must receive cues to instruct their homing to and entry into the thymus and, once there, positive and negative selection signals need to be synchronized with signals that control the migration of thymocytes within and out of the thymus. This Review focuses on recent advances in our understanding of thymocyte migration and highlights some outstanding questions.

Yang and colleagues report that MAIT cells are present in the meninges where they play an essential role in repressing tissue ROS accumulation and preserving meningeal barrier integrity.

Single-cell technologies have unveiled a complex understanding of NK cells that has led to variations in nomenclature and inconsistencies across the scientific literature. Here, Vivier and colleagues used these technologies to dissect the heterogeneity of NK cells, revealing three prominent NK cell subsets in healthy human blood.

The Global Thymus Network convened virtually for ThymUS 2020 on 3–4 November 2020. Participants shared recent advances in thymus biology and enjoyed a reprieve from 2020 stressors.