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Increasing evidence indicates close interaction between immune cells and the brain, revising the traditional view of the immune privilege of the brain. However, the specific mechanisms by which immune cells promote normal neural function are not entirely understood. Mucosal-associated invariant T cells (MAIT cells) are a unique type of innate-like T cell with molecular and functional properties that remain to be better characterized. In the present study, we report that MAIT cells are present in the meninges and express high levels of antioxidant molecules. MAIT cell deficiency in mice results in the accumulation of reactive oxidative species in the meninges, leading to reduced expression of junctional protein and meningeal barrier leakage. The presence of MAIT cells restricts neuroinflammation in the brain and preserves learning and memory. Together, our work reveals a new functional role for MAIT cells in the meninges and suggests that meningeal immune cells can help maintain normal neural function by preserving meningeal barrier homeostasis and integrity.

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.

Stem cells are maintained by transcriptional programs that promote self-renewal and repress differentiation. Here, we found that the transcription factor c-Myb was essential for generating and maintaining stem cells in the CD8+ T cell memory compartment. Following viral infection, CD8+ T cells lacking Myb underwent terminal differentiation and generated fewer stem cell-like central memory cells than did Myb-sufficient T cells. c-Myb acted both as a transcriptional activator of Tcf7 (which encodes the transcription factor Tcf1) to enhance memory development and as a repressor of Zeb2 (which encodes the transcription factor Zeb2) to hinder effector differentiation. Domain-mutagenesis experiments revealed that the transactivation domain of c-Myb was necessary for restraining differentiation, whereas its negative regulatory domain was critical for cell survival. Myb overexpression enhanced CD8+ T cell memory formation, polyfunctionality and recall responses that promoted curative antitumor immunity after adoptive transfer. These findings identify c-Myb as a pivotal regulator of CD8+ T cell stemness and highlight its therapeutic potential.

Maui, Hawaii, was the home for the latest Global Thymus Network meeting 5-9 June 2016. Participants gathered together to discuss how one little organ can have such huge effects.

Signaling by the transmembrane receptor Notch is critical for T lineage development, but progenitor subsets that first receive Notch signals have not been defined. Here we identify an immature subset of early T lineage progenitors (ETPs) in the thymus that expressed the tyrosine kinase receptor Flt3 and had preserved B lineage potential at low progenitor frequency. Notch signaling was active in ETPs and was required for generation of the ETP population. Additionally, Notch signals contributed to the subsequent differentiation of ETPs. In contrast, multipotent hematopoietic progenitors circulated in the blood even in the absence of Notch signaling, suggesting that critical Notch signals during early T lineage development are delivered early after thymic entry.

Early T lineage progenitors (ETPs) in the thymus are thought to develop from common lymphoid progenitors (CLPs) in the bone marrow (BM). We compared thymic ETPs to BM CLPs in mice and found that they differed in several respects. Thymic ETPs were not interleukin 7 (IL-7)-responsive and generated B lineage progeny with delayed kinetics, whereas BM CLPs were IL-7-responsive and rapidly generated B cells. ETPs sustained production of T lineage progeny for longer periods of time than BM CLPs. Analysis of Ikaros-deficient mice that exhibit ongoing thymopoiesis without B lymphopoeisis revealed near-normal frequencies of thymic ETPs, yet undetectable numbers of BM CLPs. We conclude that ETPs can develop via a CLP-independent pathway.

International audience; Notch signaling induces gene expression of the T cell lineage and discourages alternative fate outcomes. Hematopoietic deficiency in the Notch target Hes1 results in severe T cell lineage defects; however, the underlying mechanism is unknown. We found here that Hes1 constrained myeloid gene-expression programs in T cell progenitor cells, as deletion of the myeloid regulator C/EBP-α restored the development of T cells from Hes1-deficient progenitor cells. Repression of Cebpa by Hes1 required its DNA-binding and Groucho-recruitment domains. Hes1-deficient multipotent progenitor cells showed a developmental bias toward myeloid cells and dendritic cells after Notch signaling, whereas Hes1-deficient lymphoid progenitor cells required additional cytokine signaling for diversion into the myeloid lineage. Our findings establish the importance of constraining developmental programs of the myeloid lineage early in T cell development.

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.

The thymus is seeded via the blood, but the identity of hematopoietic progenitors with access to the circulation in adult mice is unknown. We report here that the only progenitors in blood with efficient T lineage potential were lineage negative with high expression of stem cell antigen 1 and c-Kit (LSK cells). The blood LSK population, like its counterpart in the bone marrow, contained hematopoietic stem cells and nonrenewing, multipotent progenitors, including early lymphoid progenitors and CD62L(+) cells previously described as efficient T lineage progenitors. Common lymphoid progenitors could not be identified in the circulation, suggesting they are not physiological T lineage precursors. We conclude that blood LSK cells are the principal circulating progenitors with T lineage potential.