Biology subjects

Jarjour, N. N.

Publications and source records attributed to Jarjour, N. N..

6 recordsLinked to original sources

bioRxiv2025

Bhlhe40 Coordinates T Cell Programs with Distinct CD4 and CD8 T Cell Requirements for Anti-PD-1 Versus Anti-CTLA-4

The transcriptional programs enabling T cells to mediate anti-tumor immunity remain incompletely defined. Here, we identify Bhlhe40 as a key transcriptional regulator that coordinates both CD4 and CD8 T cell effector programs, revealing divergent cell-specific requirements during anti-PD-1 versus anti-CTLA-4 immune checkpoint therapy (ICT). Using conditional knockout mice, we show that anti-PD-1 efficacy depends on CD8 T cell-intrinsic Bhlhe40, whereas anti-CTLA-4 remains effective through Bhlhe40-dependent CD4 T cell Th1 programs that buffer impaired effector function in Bhlhe40-deficient CD8 T cells. Mechanistically, loss of Bhlhe40 reduces IFN-{gamma} production and skews CD8 T cells toward TCF-1-expressing progenitor exhausted/stem-like states at the expense of effector differentiation, impairing glycolytic fitness under both therapies and mitochondrial function during anti-PD-1 treatment, thereby revealing a Bhlhe40-dependent coupling between effector differentiation, cytokine production, and metabolic fitness that is particularly critical for anti-PD-1 efficacy. CD8 T cell-intrinsic Bhlhe40 also promotes critical ICT-induced remodeling from M2-like CX3CR1 macrophages to inflammatory iNOS macrophages. Analysis of human cancer datasets supported our preclinical observations, revealing that BHLHE40 is enriched in tumor-reactive and activated/exhausted CD8 T cells, where its expression is inversely correlated with TCF7 (TCF-1) and positively associated with TOX, GZMB, and IFNG. Moreover, persistent CD8 T cell clones from basal cell carcinoma responders exhibited significantly higher BHLHE40 expression at pre-treatment than those from non-responders to PD-1 blockade. Together, these findings establish Bhlhe40 not only as a transcriptional coordinator of T cell effector programs, but also as a therapy-specific, subset-dependent determinant that differentially governs CD4 and CD8 T cell contributions to anti-PD-1 and anti-CTLA-4 efficacy.

immunology↗

bioRxiv2025

Gut bacteria gatekeep host-specific colonization of a commensal fungus that boosts type 2 immunity

Naturalized, wilded, wildling, and dirty/pet store mouse models represent a spectrum of approaches designed to make laboratory mice more immunologically and physiologically similar to wild or human contexts by increasing their exposure to naturally occurring microbes and pathogens. In this study, we screened the gut mycobiome of pet store mice, and identified Kazachstania pintolopesii as a dominant fungus in pet store mice across various geographical locations. K. pintolopesii strains isolated from mice in geographically distinct pet stores stably colonize the gastrointestinal tract of laboratory mice, independent of gut bacterial composition, maintaining high fungal burdens for extended periods. K. pintolopesii rapidly became the dominant fungus in the mouse gut in conventional, antibiotic, and germ-free settings, outcompeting other non-murine fungal strains. Pet store-derived K. pintolopesii exhibited unique immunological properties distinct from typical anti-fungal responses. Unlike C. albicans colonization, K. pintolopesii did not induce circulating neutrophil expansion or Th17 cell populations in the gut mucosa. When administered systemically, K. pintolopesii-infected mice showed 100% survival with minimal fungal burden in kidneys, contrasting sharply with lethal C. albicans infections. Adaptive immune deficiency (Rag1 knockout mice) did not affect K. pintolopesii colonization or host response, indicating that B and T cell-mediated immunity does not restrain this fungus. K. pintolopesii colonization provided no cross-protection against systemic candidiasis further establishing lack of immune activation. These findings demonstrate that K. pintolopesii establishes a benign host-fungal relationship through neutrophil-independent mechanisms, avoiding classical anti-fungal immune activation while maintaining stable gut colonization. Instead, it selectively induces strong type 2 mucosal immune responses, increasing tuft and goblet cell counts and stimulating Th2 and group 2 innate lymphoid cell (ILC2) populations. This immune profile confers notable protection against intestinal nematode infection, demonstrated by reduced Heligmosomoides polygyrus egg counts. Altogether, K. pintolopesii serves as an exemplary model for commensal mycobiota, revealing distinct mechanisms for host tolerance and immune modulation.

microbiology↗

bioRxiv2024

Steady-state, therapeutic, and helminth-induced IL-4 compromise protective CD8 T cell bystander activation

Memory CD8 T cells (Tmem) can be activated into innate-like killers by cytokines like IL-12, IL-15, and/or IL-18; but mechanisms regulating this phenomenon (termed bystander activation) are not fully resolved. We found strain-intrinsic deficiencies in bystander activation using specific pathogen-free mice, whereby basal IL-4 signals antagonize IL-18 sensing. We show that therapeutic and helminth-induced IL-4 impairs protective bystander-mediated responses against pathogens. However, this IL-4/IL-18 axis does not completely abolish bystander activation but rather tunes the expression of direct versus indirect mediators of cytotoxicity (granzymes and interferon-{gamma}, respectively). We show that antigen-experience overrides strain-specific deficiencies in bystander activation, leading to uniform IL-18 receptor expression and enhanced capacity for bystander activation/cytotoxicity. Our data highlight that bystander activation is not a binary process but tuned/deregulated by other cytokines that are elevated by contemporaneous infections. Further, our findings underscore the importance of antigen-experienced Tmem to dissect the contributions of bystander Tmem in health and disease.

immunology↗

bioRxiv2024

Collaboration between IL-7 and IL-15 enables adaptation of tissue-resident and circulating memory CD8+ T cells

Interleukin-7 (IL-7) is considered a critical regulator of memory CD8+ T cell homeostasis, but this is primarily based on analysis of circulating and not tissue-resident memory (TRM) subsets. Furthermore, the cell-intrinsic requirement for IL-7 signaling during memory homeostasis has not been directly tested. Using inducible deletion, we found that Il7ra loss had only a modest effect on persistence of circulating memory and TRM subsets and that IL-7R was primarily required for normal basal proliferation. Loss of IL-15 signaling imposed heightened IL-7R dependence on memory CD8+ T cells, including TRM populations previously described as IL-15-independent. In the absence of IL-15 signaling, IL-7R was upregulated, and loss of IL-7R signaling reduced proliferation in response to IL-15, suggesting cross-regulation in memory CD8+ T cells. Thus, across subsets and tissues, IL-7 and IL-15 act in concert to support memory CD8+ T cells, conferring resilience to altered availability of either cytokine. HighlightsTissue-resident and circulating memory CD8+ T cells modestly decline after loss of IL-7R IL-7R is required for normal self-renewal of memory CD8+ T cells Combined loss of IL-7 and IL-15 causes a profound defect across memory CD8+ T cell subsets Cross-regulation of IL-7 and IL-15 signaling occurs in memory CD8+ T cells O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=70 SRC="FIGDIR/small/596695v1_ufig1.gif" ALT="Figure 1"> View larger version (17K): org.highwire.dtl.DTLVardef@8e439corg.highwire.dtl.DTLVardef@1f8e42forg.highwire.dtl.DTLVardef@14cfceforg.highwire.dtl.DTLVardef@171e4eb_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2022

An Open Microfluidic Coculture Model of Fibroblasts and Eosinophils to Investigate Mechanisms of Airway Inflammation

Interactions between fibroblasts and immune cells play an important role in tissue inflammation. Previous studies have found that eosinophils activated with interleukin-3 (IL-3) degranulate on aggregated immunoglobulin G (IgG) and release mediators that activate fibroblasts in the lung. However, these studies were done with eosinophil-conditioned media that have the capacity to investigate only one-way signaling from eosinophils to fibroblasts. Here, we demonstrate a coculture model of primary normal human lung fibroblasts (HLFs) and human blood eosinophils from patients with allergy and asthma using an open microfluidic coculture device. In our device, the two types of cells can communicate via two-way soluble factor signaling in the shared media while being physically separated by a half wall. Initially, we assessed the level of eosinophil degranulation by their release of eosinophil-derived neurotoxin (EDN). Next, we analyzed the inflammation-associated genes and soluble factors using reverse transcription quantitative polymerase chain reaction (RT-qPCR) and multiplex immunoassays, respectively. Our results suggest an induction of a proinflammatory fibroblast phenotype of HLFs following the coculture with degranulating eosinophils, validating our previous findings. Additionally, we present a new result that indicate potential impacts of activated HLFs back on eosinophils. This open microfluidic coculture platform provides unique opportunities to investigate the intercellular signaling between the two cell types and their roles in airway inflammation and remodeling.

cell biology↗

bioRxiv2019

Deficiency in Bhlhe40 impairs resistance to H. polygyrus bakeri and reveals novel Csf2rb-dependent regulation of anti-helminth immunity

The cytokines GM-CSF and IL-5 are thought to possess largely divergent functions despite a shared dependence on the common beta ({beta}C) chain to initiate signaling. Although IL-5 is part of the core type 2 cytokine signature and is required for protection against some helminths, it is dispensable for immunity to others, such as Heligmosomoides polygyrus bakeri (H. polygyrus). Whether this is due to compensatory mechanisms is unclear. The transcription factor Bhlhe40 has been shown to control GM-CSF production and is proposed to be a novel regulator of T helper type 2 cells. We have found that Bhlhe40 is required in T cells for a protective memory response to secondary H. polygyrus infection. H. polygyrus rechallenge elicited dramatic Bhlhe40-dependent changes in gene and cytokine expression by lamina propria CD4+ T cells and in vitro-polarized TH2 cells, including induction of GM-CSF and maximal production of type 2 cytokines including IL-5. {beta}C chain-deficient, but not GM-CSF-deficient, mice rechallenged with H. polygyrus had severely impaired protective immunity. Our results demonstrate that Bhlhe40 is an essential regulator of TH2 cell immunity during helminth infection and reveal unexpected redundancy of {beta}C chain-dependent cytokines.

immunology↗