B-cell acute lymphoblastic leukemia (B-ALL) reflects the malignant counterpart of developing B cells in the bone marrow (BM). Despite tremendous progress in B-ALL treatment, the overall survival of adults at diagnosis and patients at all ages after relapse remains poor. Galectin-1 (GAL1) expressed by BM supportive niches delivers proliferation signals to normal pre-B cells through interaction with the pre-B cell receptor (pre-BCR). Here, we asked whether GAL1 gives non-cell autonomous signals to pre-BCR+ pre-B ALL, in addition to cell-autonomous signals linked to genetic alterations. In syngeneic and patient-derived xenograft (PDX) murine models, murine and human pre-B ALL development is influenced by GAL1 produced by BM niches through pre-BCR-dependent signals, similarly to normal pre-B cells. Furthermore, targeting pre-BCR signaling together with cell-autonomous oncogenic pathways in pre-B ALL PDX improved treatment response. Our results show that non-cell autonomous signals transmitted by BM niches represent promising targets to improve B-ALL patient survival.
© 2023 The Author(s).

Although single-cell RNA sequencing studies have begun to provide compendia of cell expression profiles1-9, it has been difficult to systematically identify and localize all molecular cell types in individual organs to create a full molecular cell atlas. Here, using droplet- and plate-based single-cell RNA sequencing of approximately 75,000 human cells across all lung tissue compartments and circulating blood, combined with a multi-pronged cell annotation approach, we create an extensive cell atlas of the human lung. We define the gene expression profiles and anatomical locations of 58 cell populations in the human lung, including 41 out of 45 previously known cell types and 14 previously unknown ones. This comprehensive molecular atlas identifies the biochemical functions of lung cells and the transcription factors and markers for making and monitoring them; defines the cell targets of circulating hormones and predicts local signalling interactions and immune cell homing; and identifies cell types that are directly affected by lung disease genes and respiratory viruses. By comparing human and mouse data, we identified 17 molecular cell types that have been gained or lost during lung evolution and others with substantially altered expression profiles, revealing extensive plasticity of cell types and cell-type-specific gene expression during organ evolution including expression switches between cell types. This atlas provides the molecular foundation for investigating how lung cell identities, functions and interactions are achieved in development and tissue engineering and altered in disease and evolution.

HIV viral reservoirs are established very early during infection. Resident memory T cells (TRM) are present in tissues such as the lower female genital tract, but the contribution of this subset of cells to the pathogenesis and persistence of HIV remains unclear. Here, we show that cervical CD4+TRM display a unique repertoire of clusters of differentiation, with enrichment of several molecules associated with HIV infection susceptibility, longevity and self-renewing capacities. These protein profiles are enriched in a fraction of CD4+TRM expressing CD32. Cervical explant models show that CD4+TRM preferentially support HIV infection and harbor more viral DNA and protein than non-TRM. Importantly, cervical tissue from ART-suppressed HIV+ women contain high levels of viral DNA and RNA, being the TRM fraction the principal contributor. These results recognize the lower female genital tract as an HIV sanctuary and identify CD4+TRM as primary targets of HIV infection and viral persistence. Thus, strategies towards an HIV cure will need to consider TRM phenotypes, which are widely distributed in tissues.

T follicular helper (Tfh)-like cells with potent B-cell helping ability are mobilized into human circulation after parenteral vaccination and are generally held to reflect ongoing germinal center reactions. However, whether mucosal vaccination induces systemic Tfh responses and how such responses may relate to IgA production are unknown. We investigated the frequencies, phenotype and function of circulating Tfh-like CD4+CXCR5+ T cells (cTfh) in adults receiving an oral inactivated enterotoxigenic Escherichia coli vaccine. Subjects were classified as vaccine responders or weak/non-responders based on their intestine-derived antibody-secreting cell (ASC) IgA responses to major vaccine antigens. Oral immunization induced significantly increased proportions of cTfh cells expressing the cTfh activation marker inducible costimulator (ICOS) in ASC responders, but not in weak/non-responders. Vaccination also enhanced the expression of IL-21, Th17 markers and integrin β7 by activated cTfh cells, supporting functionality and gut homing potential. cTfh cells promoted total and vaccine specific IgA production from cocultured B cells. Magnitudes of cTfh responses assessed within a week after primary vaccinations correlated with memory intestine-derived vaccine specific IgA responses 1-2 years later. We conclude that activated ICOS+ Tfh-like cells are mobilized into blood after oral vaccination and may be used as biomarkers of vaccine specific mucosal memory in humans.

Preferential infection and depletion of gut-homing α4β7 CD4+ T cells in the blood are observed in chronic HIV/SIV infection. The dynamic change in gut-homing α4β7 CD4+ T cells and their functional subsets during the acute stages of HIV-1 infection are less documented. Therefore, we conducted a cohort study to investigate whether acute HIV-1 infection induced abnormalities in gut-homing α4β7 CD4+ T cells and their functional subsets. We examined the frequency, absolute number, and functionality of gut-homing α4β7 CD4+ T cells in 26 acute HIV-1-infected patients compared with 20 healthy individuals. We found that circulating gut-homing α4β7 CD4+ T cells were preferentially depleted during acute HIV-1 infection and were positively correlated with absolute CD4+ T-cell count in blood. Notably, Th17 and Th1 cell subsets of gut-homing CD4+ T cells were also decreased, which resulted in an imbalance of T helper cells (Th1):regulatory T cells (Treg) and Treg:Th17 ratios. Gut-homing Th17 and Th1 cells were also positively correlated with the absolute number of total CD4+ T cells and gut-homing CD4+ T cells. The gut-homing Treg:Th17 ratio was inversely correlated with the CD4+ T-cell count. Taken together, the analyses of our acute HIV-1 cohort demonstrate that gut-homing α4β7 CD4+ T cells and their functional subsets were profoundly depleted during acute HIV-1 infection, which may have resulted in the persistent loss of circulating CD4+ T cells and an imbalance of Th1:Treg and Treg:Th17 ratios and contribute to HIV-1 disease pathogenesis.