Biology subjects

Chakraverty, R.

Publications and source records attributed to Chakraverty, R..

5 recordsLinked to original sources

bioRxiv2026

A combined program of induced stemness and differentiation in response to interferon gamma drives acute myeloid leukaemia growth

How inflammation shapes acute myeloid leukaemia (AML) has come under scrutiny, as it may explain the disease resistance to immunotherapy approaches. IFNg has emerged as a key cytokine with paradoxical roles in suppressing and supporting AML growth, and the fundamental question of how leukemic stem cells (LSCs) respond to IFNg and whether IFNg signaling influences LSC quiescence and their capacity to regenerate disease over the long term remains unanswered. Here, we study primary human AML cells and murine models and combine bioinformatics analyses and functional assays to show that AML hierarchical heterogeneity is responsive to IFNg challenge. We uncover that IFNg triggers parallel stemness and differentiation programs; HSC/MPP-like cells enter deeper stemness, associated with quiescence and high leukaemia regeneration potential, while the surviving pool of progenitor-like cells divides faster but produces progeny that is quickly lost. Finally, with murine models we show that exposure to inflammation in vivo results in only transient impairment of leukaemia propagating capacity. This mechanism is driven by a previously unrecognised intraclonal fate bifurcation, relevant for the development of more effective therapeutic approaches.

cancer biology↗

bioRxiv2026

KLRG1 identifies circulating cytotoxic CD4 T cells with selective anti-tumor function in human cancer

Given the critical role of CD4 T cells in anti-tumor immunity, strategies to harness these cells for cancer immunotherapy are gaining increasing interest. Historically overshadowed by CD8 T cells, cytotoxic CD4 T cells can directly kill MHC class II-expressing tumor cells. However, the defining molecular signature and the mechanisms underlying their cytolytic activity remain poorly understood, particularly in cancer patients. Here, using ex vivo single-cell transcriptomic and spatial analyses of CD4 T cells from paired blood and tumor samples of melanoma patients, we identified Killer Cell Lectin-Like Receptor G1 (KLRG1) as a defining surface marker of cytotoxic CD4 T cells. The CD4+ KLRG1+ T cell subset was notably enriched among circulating cells compared with tumor-infiltrating populations, which were instead enriched in T follicular helper (Tfh) states. Functionally, KLRG1+ CD4 T cells expressed elevated levels of cytotoxic genes and exhibited superior tumor-killing capacity compared with their KLRG1- counterparts. We demonstrated that their cytotoxicity is granulysin-dependent, as confirmed by CRISPR/Cas9-mediated gene deletion. Mechanistically, CD4 T cells spared MHC class II+ cells lacking the KLRG1 ligands CD324 and CD325, such as professional antigen-presenting cells (APCs), indicating that cytotoxicity was selectively directed towards tumor cells while preserving immune cells. Finally, by investigating how the tumor microenvironment may impair CD4 T cell cytotoxicity, we showed that tumor-derived factors, including interleukin-6 (IL-6), are key drivers promoting the transition of cytotoxic CD4 T cells toward a Tfh phenotype. In summary, our findings define KLRG1 as a defining cell surface marker of cytotoxic CD4 T cells in cancer patients, as well as a key regulator that protects MHC class II+ APCs. Moreover, targeting the IL-6 signalling pathway may enhance CD4 T cell anti-tumor cytotoxicity, offering new avenues for cancer immunotherapy.

immunology↗

bioRxiv2020

Dynamic regulation of hierarchical heterogeneity in Acute Myeloid Leukemia serves as a tumor immunoevasion mechanism

Acute Myeloid Leukemia, a hematological malignancy with poor clinical outcome, is composed of hierarchically heterogeneous cells. We examine the contribution of this heterogeneity to disease progression in the context of anti-tumor immune responses and investigate whether these responses regulate the balance between stemness and differentiation in AML. Combining phenotypic analysis with proliferation dynamics and fate-mapping of AML cells in a murine AML model, we demonstrate the presence of a terminally differentiated, chemoresistant population expressing high levels of PDL1. We show that PDL1 upregulation in AML cells, following exposure to IFN{gamma} from activated T cells, is coupled with AML differentiation and the dynamic balance between proliferation, versus differentiation and immunosuppression, facilitates disease progression in the presence of immune responses. This microenvironment-responsive hierarchical heterogeneity in AML may be key in facilitating disease growth at the population level at multiple stages of disease, including following bone marrow transplantation and immunotherapy.

cancer biology↗

bioRxiv2019

A single wave of monocytes is sufficient to replenish the long-term Langerhans cell network after immune injury

Embryo-derived Langerhans cells (eLC) are maintained within the sealed epidermis without contribution from circulating cells. When the network is perturbed by transient exposure to ultra-violet light, short-term LC are temporarily reconstituted from an initial wave of monocytes, but thought to be superseded by more permanent repopulation with undefined LC precursors. However, the extent to which this mechanism is relevant to immune-pathological processes that damage LC population integrity is not known. Using a model of allogeneic hematopoietic stem cell transplantation, where allo-reactive T cells directly target eLC, we have asked if and how the original LC network is ultimately restored. We find that donor monocytes, but not dendritic cells, are the precursors of the long-term LC in this context. Destruction of eLC leads to recruitment of a single wave of monocytes which engraft in the epidermis and undergo a sequential pathway of differentiation via transcriptionally distinct EpCAM+ precursors. Monocyte-derived LC acquire the capacity of self-renewal, and turn-over in the epidermis was remarkably similar to that of steady state eLC. However, we have identified a bottleneck in the differentiation and survival of epidermal monocytes, which together with the slow turn-over of mature LC limits repair of the network. Furthermore, replenishment of the LC network leads to constitutive entry of cells into the epidermal compartment. Thus, immune injury triggers functional adaptation of mechanisms used to maintain tissue-resident macrophages at other sites, but this process is highly inefficient in the skin.\n\nHighlightsO_LIImmune injury leads to recruitment of a single wave of monocytes to replace resident Langerhans cells (LC).\nC_LIO_LIDC lineage cells cannot become long-term replacement LC.\nC_LIO_LIThe size of the re-emerging network is controlled by density-dependent division of mature LC.\nC_LIO_LIImmune injury and inefficient repopulation by monocyte-derived cells lead to a permanently altered LC niche.\nC_LI\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=107 SRC=\"FIGDIR/small/617514v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (32K):\norg.highwire.dtl.DTLVardef@1c08563org.highwire.dtl.DTLVardef@753e0corg.highwire.dtl.DTLVardef@13ca3cforg.highwire.dtl.DTLVardef@269ffc_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2019

The obese liver environment mediates conversion of NK cells to a less cytotoxic ILC1-like phenotype

The liver contains both NK cells and their less cytotoxic relatives, ILC1. Here, we investigate the role of NK cells and ILC1 in the obesity-associated condition, non-alcoholic fatty liver disease (NAFLD). In the livers of mice suffering from NAFLD, NK cells are less able to degranulate, express lower levels of perforin and are less able to kill cancerous target cells than those from healthy animals. This is associated with a decreased ability to kill cancer cells in vivo. On the other hand, we find that perforin-deficient mice suffer from less severe NAFLD, suggesting that this reduction in NK cell cytotoxicity may be protective in the obese liver, albeit at the cost of increased susceptibility to cancer. The decrease in cytotoxicity is associated with a shift towards a transcriptional profile characteristic of ILC1, increased expression of the ILC1-associated proteins CD200R1 and CD49a, and an altered metabolic profile mimicking that of ILC1. We show that the conversion of NK cells to this less cytotoxic phenotype is at least partially mediated by TGF{beta}, which is expressed at high levels in the obese liver. Finally, we show that reduced cytotoxicity is also a feature of NK cells in the livers of human NAFLD patients.

immunology↗