Browsing by Subject "T-Lymphocytes"

Now showing 1 - 10 of 15
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    All in for nuclear PFKP–induced CXCR4 metastasis: a T cell acute lymphoblastic leukemia prognostic marker
    (The American Society for Clinical Investigation, 2021) Broxmeyer, Hal E.; Microbiology and Immunology, School of Medicine
    Phosphofructokinase 1 (PFK1) is expressed in T cell acute lymphoblastic leukemia (T-ALL), where its upregulation is linked with cancer progression. While PFK1 functions in the glycolysis pathway within the cytoplasm, it is also present in the nucleus where it regulates gene transcription. In this issue of the JCI, Xueliang Gao, Shenghui Qin, et al. focus their mechanism-based investigation on the nucleocytoplasmic shuttling aspect of the PFK1 platelet isoform, PFKP. Functional nuclear export and localization sequences stimulated CXC chemokine receptor type 4 (CXCR4) expression to promote T-ALL invasion that involved cyclin D3/CDK6, c-Myc, and importin-9. Since the presence of nuclear PFKP is associated with poor survival in T-ALL, nuclear PFKP-induced CXCR4 expression might serve as a prognostic marker for T-ALL. More promising, though, are the mechanistic insights suggesting that approaches to dampening metastatic migration may have application to benefit patients with T-ALL.
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    Antigen-specific T cell responses correlate with decreased occurrence of acute GVHD in a multicenter contemporary cohort
    (Springer Nature, 2022) Cruz, Conrad Russell Y.; Bo, Na; Bakoyannis, Giorgos; Wright, Kaylor E.; Chorvinsky, Elizabeth A.; Powell, Allison; Bollard, Catherine M.; Jacobsohn, David; Cooke, Kenneth R.; Duncan, Christine; Krance, Robert M.; Carpenter, Paul A.; Rowan, Courtney M.; Paczesny, Sophie; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public Health
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    ATG5-Dependent Autophagy Uncouples T-cell Proliferative and Effector Functions and Separates Graft-versus-Host Disease from Graft-versus-Leukemia
    (American Association for Cancer Research, 2021) Oravecz-Wilson, Katherine; Rossi, Corinne; Zajac, Cynthia; Sun, Yaping; Li, Lu; Decoville, Thomas; Fujiwara, Hideaki; Kim, Stephanie; Peltier, Daniel; Reddy, Pavan; Medicine, School of Medicine
    Autophagy is a vital cellular process whose role in T immune cells is poorly understood, specifically, in its regulation of allo-immunity. Stimulation of wild-type T cells in vitro and in vivo with allo-antigens enhances autophagy. To assess the relevance of autophagy to T-cell allo-immunity, we generated T-cell-specific Atg5 knock-out mice. Deficiency of ATG5-dependent autophagy reduced T-cell proliferation and increased apoptosis following in vitro and in vivo allo-stimulation. The absence of ATG5 in allo-stimulated T cells enhanced their ability to release effector cytokines and cytotoxic functions, uncoupling their proliferation and effector functions. Absence of autophagy reduced intracellular degradation of cytotoxic enzymes such as granzyme B, thus enhancing the cytotoxicity of T cells. In several in vivo models of allo-HSCT, ATG5-dependent dissociation of T-cell functions contributed to significant reduction in graft-versus-host disease (GVHD) but retained sufficient graft versus tumor (GVT) response. Our findings demonstrate that ATG5-dependent autophagy uncouples T-cell proliferation from its effector functions and offers a potential new strategy to enhance outcomes after allo-HSCT. SIGNIFICANCE: These findings demonstrate that induction of autophagy in donor T-cell promotes GVHD, while inhibition of T-cell autophagy mitigates GVHD without substantial loss of GVL responses.
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    Caspofungin Increases Fungal Chitin and Eosinophil and γδ T Cell-Dependent Pathology in Invasive Aspergillosis
    (American Association of Immunologists, 2017-07-15) Amarsaikhan, Nansalmaa; Sands, Ethan M.; Shah, Anand; Abdolrasouli, Ali; Reed, Anna; Slaven, James E.; Armstrong-James, Darius; Templeton, Steven P.; Microbiology and Immunology, School of Medicine
    The polysaccharide-rich fungal cell wall provides pathogen-specific targets for antifungal therapy and distinct molecular patterns that stimulate protective or detrimental host immunity. The echinocandin antifungal caspofungin inhibits synthesis of cell wall β-1,3-glucan and is used for prophylactic therapy in immune-suppressed individuals. However, breakthrough infections with fungal pathogen Aspergillus fumigatus are associated with caspofungin prophylaxis. In this study, we report in vitro and in vivo increases in fungal surface chitin in A. fumigatus induced by caspofungin that was associated with airway eosinophil recruitment in neutropenic mice with invasive pulmonary aspergillosis (IA). More importantly, caspofungin treatment of mice with IA resulted in a pattern of increased fungal burden and severity of disease that was reversed in eosinophil-deficient mice. Additionally, the eosinophil granule proteins major basic protein and eosinophil peroxidase were more frequently detected in the bronchoalveolar lavage fluid of lung transplant patients diagnosed with IA that received caspofungin therapy when compared with azole-treated patients. Eosinophil recruitment and inhibition of fungal clearance in caspofungin-treated mice with IA required RAG1 expression and γδ T cells. These results identify an eosinophil-mediated mechanism for paradoxical caspofungin activity and support the future investigation of the potential of eosinophil or fungal chitin-targeted inhibition in the treatment of IA.
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    IFN-γ and IL-21 Double Producing T Cells Are Bcl6-Independent and Survive into the Memory Phase in Plasmodium chabaudi Infection
    (Public Library of Science (PLoS), 2015) Carpio, Victor H.; Opata, Michael M.; Montañez, Marelle E.; Banerjee, Pinaki P.; Dent, Alexander L.; Stephens, Robin; Department of Microbiology and Immunology, IU School of Medicine
    CD4 T cells are required to fight malaria infection by promoting both phagocytic activity and B cell responses for parasite clearance. In Plasmodium chabaudi infection, one specific CD4 T cell subset generates anti-parasitic IFN-γ and the antibody-promoting cytokine, IL-21. To determine the lineage of these multifunctional T cells, we followed IFN-γ+ effector T cells (Teff) into the memory phase using Ifng-reporter mice. While Ifng+ Teff expanded, the level of the Th1 lineage-determining transcription factor T-bet only peaked briefly. Ifng+ Teff also co-express ICOS, the B cell area homing molecule CXCR5, and other Tfh lineage-associated molecules including Bcl6, the transcription factor required for germinal center (GC) T follicular helper cells (Tfh) differentiation. Because Bcl6 and T-bet co-localize to the nucleus of Ifng+ Teff, we hypothesized that Bcl6 controls the Tfh-like phenotype of Ifng+ Teff cells in P. chabaudi infection. We first transferred Bcl6-deficient T cells into wildtype hosts. Bcl6-deficient T cells did not develop into GC Tfh, but they still generated CXCR5+ IFN-γ+ IL-21+ IL-10+ Teff, suggesting that this predominant population is not of the Tfh-lineage. IL-10 deficient mice, which have increased IFN-γ and T-bet expression, demonstrated expansion of both IFN-γ+ IL-21+ CXCR5+ cells and IFN-γ+ GC Tfh cells, suggesting a Th1 lineage for the former. In the memory phase, all Ifng+ T cells produced IL-21, but only a small percentage of highly proliferative Ifng+ T cells maintained a T-bethi phenotype. In chronic malaria infection, serum IFN-γ correlates with increased protection, and our observation suggests Ifng+ T cells are maintained by cellular division. In summary, we found that Ifng+ T cells are not strictly Tfh derived during malaria infection. T cells provide the host with a survival advantage when facing this well-equipped pathogen, therefore, understanding the lineage of pivotal T cell players will aid in the rational design of an effective malaria vaccine.
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    Insulin Receptor-Expressing T Cells Appear in Individuals at Risk for Type 1 Diabetes and Can Move into the Pancreas in C57BL/6 Transgenic Mice
    (American Association of Immunologists, 2021) Nandedkar-Kulkarni, Neha; Esakov, Emily; Gregg, Brigid; Atkinson, Mark A.; Rogers, Douglas G.; Horner, James D.; Singer, Kanakadurga; Lundy, Steven K.; Felton, Jamie L.; Al-Huniti, Tasneem; Kalinoski, Andrea Nestor; Morran, Michael P.; Gupta, Nirdesh K.; Bretz, James D.; Balaji, Swapnaa; Chen, Tian; McInerney, Marcia F.; Pediatrics, School of Medicine
    Insulin receptor (IR) expression on the T cell surface can indicate an activated state; however, the IR is also chemotactic, enabling T cells with high IR expression to physically move toward insulin. In humans with type 1 diabetes (T1D) and the NOD mouse model, a T cell-mediated autoimmune destruction of insulin-producing pancreatic β cells occurs. In previous work, when purified IR+ and IR- T cells were sorted from diabetic NOD mice and transferred into irradiated nondiabetic NOD mice, only those that received IR+ T cells developed insulitis and diabetes. In this study, peripheral blood samples from individuals with T1D (new onset to 14 y of duration), relatives at high-risk for T1D, defined by positivity for islet autoantibodies, and healthy controls were examined for frequency of IR+ T cells. High-risk individuals had significantly higher numbers of IR+ T cells as compared with those with T1D (p < 0.01) and controls (p < 0.001); however, the percentage of IR+ T cells in circulation did not differ significantly between T1D and control subjects. With the hypothesis that IR+ T cells traffic to the pancreas in T1D, we developed a (to our knowledge) novel mouse model exhibiting a FLAG-tagged mouse IR on T cells on the C57BL/6 background, which is not susceptible to developing T1D. Interestingly, these C57BL/6-CD3FLAGmIR/mfm mice showed evidence of increased IR+ T cell trafficking into the islets compared with C57BL/6 controls (p < 0.001). This transgenic animal model provides a (to our knowledge) novel platform for investigating the influence of IR expression on T cell trafficking and the development of insulitis.
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    PTEN directs developmental and metabolic signaling for innate-like T cell fate and tissue homeostasis
    (Springer Nature, 2022) Blanco, Daniel Bastardo; Chapman, Nicole M.; Raynor, Jana L.; Xu, Chengxian; Su, Wei; Anil, K. C.; Li, Wei; Lim, Seon Ah; Schattgen, Stefan; Shi, Hao; Risch, Isabel; Sun, Yu; Dhungana, Yogesh; Kim, Yunjung; Wei, Jun; Rankin, Sherri; Neale, Geoffrey; Thomas, Paul G.; Yang, Kai; Chi, Hongbo; Pediatrics, School of Medicine
    Phosphatase and tensin homologue (PTEN) is frequently mutated in human cancer, but its roles in lymphopoiesis and tissue homeostasis remain poorly defined. Here we show that PTEN orchestrates a two-step developmental process linking antigen receptor and IL-23-Stat3 signalling to type-17 innate-like T cell generation. Loss of PTEN leads to pronounced accumulation of mature IL-17-producing innate-like T cells in the thymus. IL-23 is essential for their accumulation, and ablation of IL-23 or IL-17 signalling rectifies the reduced survival of female PTEN-haploinsufficient mice that model human patients with PTEN mutations. Single-cell transcriptome and network analyses revealed the dynamic regulation of PTEN, mTOR and metabolic activities that accompanied type-17 cell programming. Furthermore, deletion of mTORC1 or mTORC2 blocks PTEN loss-driven type-17 cell accumulation, and this is further shaped by the Foxo1 and Stat3 pathways. Collectively, our study establishes developmental and metabolic signalling networks underpinning type-17 cell fate decisions and their functional effects at coordinating PTEN-dependent tissue homeostasis.
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    PU.1 expression in T follicular helper cells limits CD40L-dependent germinal center B cell development.
    (American Association of Immunologists, 2015-10-15) Awe, Olufolakemi; Hufford, Matthew M.; Wu, Hao; Pham, Duy; Chang, Hua-Chen; Jabeen, Rukhsana; Dent, Alexander L.; Kaplan, Mark H.; Department of Microbiology and Immunology, IU School of Medicine
    PU.1 is an ETS family transcription factor important for the development of multiple hematopoietic cell lineages. Previous work demonstrated a critical role for PU.1 in promoting Th9 development, and in limiting Th2 cytokine production. Whether PU.1 has functions in other T helper lineages is not clear. In this report we examined the effects of ectopic expression of PU.1 in CD4+T cells and observed decreased expression of genes involved with the function of T follicular helper (Tfh) cells, including Il21 and Tnfsf5 (encoding CD40L). T cells from conditional mutant mice that lack expression of PU.1 in T cells (Sfpi1lck−/−) demonstrated increased production of CD40L and IL-21 in vitro. Following adjuvant-dependent or adjuvant-independent immunization, we observed that Sfpi1lck−/− mice had increased numbers of Tfh cells, increased germinal center B cells, and increased antibody production in vivo. This correlated with increased expression of IL-21 and CD40L in Tfh cells from Sfpi1lck−/− mice, compared to control mice. Finally, although blockade of IL-21 did not affect germinal center B cells in Sfpi1lck−/− mice, anti-CD40L treatment of immunized Sfpi1lck−/− mice decreased germinal center B cell numbers and antigen-specific immunoglobulin concentrations. Together, these data indicate an inhibitory role of PU.1 in the function of T follicular helper cells, germinal centers, and Tfh-dependent humoral immunity.