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1. De novo construction of T cell compartment in humanized mice engrafted with iPSC-derived thymus organoids

   https://doi.org/10.1038/s41592-022-01583-3  

   Zeleniak, Ann; Wiegand, Connor; Liu, Wen; McCormick, Catherine; K., Ravikumar; Alavi, Amir; Guan, Haonan; Bertera, Suzanne; Lakomy, Robert; Tajima, Asako; et al (October 2022, Nature Methods)

   Madhura Mukhopadhyay (Ed.)

   Hematopoietic humanized (hu) mice are powerful tools for modeling the function of the human immune system and are also widely used for preclinical and drug discovery studies. However, generating a functional human T cell compartment in hu mice remains challenging, primarily due to the species-related differences between human and mouse thymus. While engrafting human fetal thymic tissues can support robust T cell development in hu mice, tissue scarcity and ethical concerns limit their wide use. Here, we describe tissue engineered human thymus organoids generated from inducible pluripotent stem cells (iPSC-thymus) that can support the de novo generation of a diverse population of functional human T cells. T cells of iPSC-thymus engrafted hu mice could mediate both cellular and humoral immune responses, including mounting robust proinflammatory responses upon TCR engagement, inhibiting allogeneic tumor graft growth and facilitating efficient Ig class switching. Our findings suggest that hu mice engrafted with iPSC-thymus can work as a novel system to study the development and function of human T cells in vivo. 

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2. How Naive T-Cell Clone Counts Are Shaped By Heterogeneous Thymic Output and Homeostatic Proliferation

   https://doi.org/10.3389/fimmu.2021.735135  

   Dessalles, Renaud; Pan, Yunbei; Xia, Mingtao; Maestrini, Davide; D’Orsogna, Maria R.; Chou, Tom (February 2022, Frontiers in Immunology)

   The specificity of T cells is that each T cell has only one T cell receptor (TCR). A T cell clone represents a collection of T cells with the same TCR sequence. Thus, the number of different T cell clones in an organism reflects the number of different T cell receptors (TCRs) that arise from recombination of the V(D)J gene segments during T cell development in the thymus. TCR diversity and more specifically, the clone abundance distribution, are important factors in immune functions. Specific recombination patterns occur more frequently than others while subsequent interactions between TCRs and self-antigens are known to trigger proliferation and sustain naive T cell survival. These processes are TCR-dependent, leading to clone-dependent thymic export and naive T cell proliferation rates. We describe the heterogeneous steady-state population of naive T cells (those that have not yet been antigenically triggered) by using a mean-field model of a regulated birth-death-immigration process. After accounting for random sampling, we investigate how TCR-dependent heterogeneities in immigration and proliferation rates affect the shape of clone abundance distributions (the number of different clones that are represented by a specific number of cells, or “clone counts”). By using reasonable physiological parameter values and fitting predicted clone counts to experimentally sampled clone abundances, we show that realistic levels of heterogeneity in immigration rates cause very little change to predicted clone-counts, but that modest heterogeneity in proliferation rates can generate the observed clone abundances. Our analysis provides constraints among physiological parameters that are necessary to yield predictions that qualitatively match the data. Assumptions of the model and potentially other important mechanistic factors are discussed. 

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3. Somatic hypermutation of T cell receptor α chain contributes to selection in nurse shark thymus

   https://doi.org/10.7554/eLife.28477  

   Ott, Jeannine A; Castro, Caitlin D; Deiss, Thaddeus C; Ohta, Yuko; Flajnik, Martin F; Criscitiello, Michael F (April 2018, eLife)

   Since the discovery of the T cell receptor (TcR), immunologists have assigned somatic hypermutation (SHM) as a mechanism employed solely by B cells to diversify their antigen receptors. Remarkably, we found SHM acting in the thymus on α chain locus of shark TcR. SHM in developing shark T cells likely is catalyzed by activation-induced cytidine deaminase (AID) and results in both point and tandem mutations that accumulate non-conservative amino acid replacements within complementarity-determining regions (CDRs). Mutation frequency at TcRα was as high as that seen at B cell receptor loci (BcR) in sharks and mammals, and the mechanism of SHM shares unique characteristics first detected at shark BcR loci. Additionally, fluorescence in situ hybridization showed the strongest AID expression in thymic corticomedullary junction and medulla. We suggest that TcRα utilizes SHM to broaden diversification of the primary αβ T cell repertoire in sharks, the first reported use in vertebrates. 

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4. Quantitative analyses of T cell motion in tissue reveals factors driving T cell search in tissues

   https://doi.org/10.7554/eLife.84916  

   Torres, David J; Mrass, Paulus; Byrum, Janie; Gonzales, Arrick; Martinez, Dominick N; Juarez, Evelyn; Thompson, Emily; Vezys, Vaiva; Moses, Melanie E; Cannon, Judy L (October 2023, eLife)

   T cells are required to clear infection, and T cell motion plays a role in how quickly a T cell finds its target, from initial naive T cell activation by a dendritic cell to interaction with target cells in infected tissue. To better understand how different tissue environments affect T cell motility, we compared multiple features of T cell motion including speed, persistence, turning angle, directionality, and confinement of T cells moving in multiple murine tissues using microscopy. We quantitatively analyzed naive T cell motility within the lymph node and compared motility parameters with activated CD8 T cells moving within the villi of small intestine and lung under different activation conditions. Our motility analysis found that while the speeds and the overall displacement of T cells vary within all tissues analyzed, T cells in all tissues tended to persist at the same speed. Interestingly, we found that T cells in the lung show a marked population of T cells turning at close to 180^o, while T cells in lymph nodes and villi do not exhibit this “reversing” movement. T cells in the lung also showed significantly decreased meandering ratios and increased confinement compared to T cells in lymph nodes and villi. These differences in motility patterns led to a decrease in the total volume scanned by T cells in lung compared to T cells in lymph node and villi. These results suggest that the tissue environment in which T cells move can impact the type of motility and ultimately, the efficiency of T cell search for target cells within specialized tissues such as the lung. 

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5. Tissue topography steers migrating Drosophila border cells

   https://doi.org/10.1126/science.aaz4741  

   Dai, Wei; Guo, Xiaoran; Cao, Yuansheng; Mondo, James A.; Campanale, Joseph P.; Montell, Brandon J.; Burrous, Haley; Streichan, Sebastian; Gov, Nir; Rappel, Wouter-Jan; et al (November 2020, Science)

   Moving cells can sense and respond to physical features of the microenvironment; however, in vivo, the significance of tissue topography is mostly unknown. Here, we usedDrosophilaborder cells, an established model for in vivo cell migration, to study how chemical and physical information influences path selection. Although chemical cues were thought to be sufficient, live imaging, genetics, modeling, and simulations show that microtopography is also important. Chemoattractants promote predominantly posterior movement, whereas tissue architecture presents orthogonal information, a path of least resistance concentrated near the center of the egg chamber. E-cadherin supplies a permissive haptotactic cue. Our results provide insight into how cells integrate and prioritize topographical, adhesive, and chemoattractant cues to choose one path among many. 

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