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1. The Effect of Malnutrition on T-cell Circadian Rhythms

   https://doi.org/10.4049/jimmunol.208.Supp.167.07  

   Foster, Takesha R.; Dadzie, Kwesi A; Adams, Olivia; Gubbels-Bupp, Melanie R (May 2022, The Journal of Immunology)

   Abstract In mammals, T-cell migration is under circadian control, likely to anticipate daily rhythms in infection risk. Glucocorticoids are a major controller of circadian processes and malnutrition is associated with increased glucocorticoid secretion. Previous studies suggest malnutrition may impart a “super-quiescent” phenotype to T-cells, enabling a greater number of naïve T-cells to survive short-term malnutrition albeit with diminished function. Thus, we hypothesize that malnourished T-cells may conserve energy by disengaging from rhythmic migration under circadian control and/or foregoing migration to reside in the bone marrow instead. To test this hypothesis, the total number of nucleated cells and naïve CD4+ and CD8+ T-cells in the blood, spleen, bone marrow, and brachial and mesenteric lymph nodes were enumerated by flow cytometry every four hours over the course of one day from control and malnourished mice. Additionally, expression levels of CD127 and CXCR4 in both T-cell populations and the concentration of glucocorticoids in the blood were assessed. A better understanding of how malnutrition affects the circadian rhythm of T-cell migration will not only help identify the mechanisms of how circadian rhythms work, but also how organisms’ circadian rhythms change in response to malnutrition. This knowledge of how malnutrition disrupts the circadian rhythm of T-cells may help improve vaccination strategies in malnourished children. Supported by NSF-MRI [DBI- 1920116] NSF -RUI [IOS-1951881] 

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2. Malnutrition Disrupts T Cell Migration

   https://doi.org/10.4049/jimmunol.208.Supp.167.08  

   Dadzie, Kwesi A.; Foster, Takesha R; Mister, Abigail; Goulmamine, Syreen; Gibson, David; Adams, Olivia; Gubbels-Bupp, Melanie R (May 2022, The Journal of Immunology)

   Abstract Malnutrition is associated with reductions in the number and function of T lymphocytes. Previous studies in the lab suggest that malnutrition may also impart a “super-quiescent” phenotype to T cells, perhaps affecting the efficiency of their migration within and between lymph nodes. Thus, the purpose of this study is to evaluate the effect of malnutrition on T cell migration in vivo and to characterize malnutrition-induced changes in the expression of proteins known to be important for T cell migration. To determine if malnourishment alters T cell migration in vivo, we compared lymph node entry rates of adoptively-transferred malnourished and control T cells in malnourished and control recipients. In agreement with other studies, control CD4+ T cells were more efficient than control CD8+ T cells at entering the lymph nodes. Interestingly, regardless of recipient diet, malnourished CD4+ and CD8+ T cells entered the lymph nodes at equivalent rates, suggesting that malnourishment eliminates distinct lymph node entry efficiencies for CD8+ and CD4+ T cells. We also found important differences in the expression of key proteins involved in T cell migration between malnourished and control mice. Overall, we found that malnutrition disrupts T cell migration including the distinct migration efficiencies of CD4+ and CD8+ T cells. An improved understanding of T cell-intrinsic changes that occur during malnourishment should enhance our knowledge of CD4+ and CD8+ T cell migration and shed light on how organisms adapt to malnutrition. Supported by NSF-MRI [DBI- 1920116] NSF-RUI [IOS-1951881] 

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3. Glucocorticoids redirect naive T cells to the bone marrow in malnourished mice

   https://doi.org/10.4049/jimmunol.210.Supp.239.07  

   Pearson, Caroline; Saravanan, Rithanya; Marczak, Marissa; Washington, Aja; Foster, Takesha R; Dadzie, Nana; Hanes, Jacob; Moore, Lindsay; Mister, Abigail; Goulmamine, Syreen; et al (May 2023, The Journal of Immunology)

   Abstract Glucocorticoids contribute to the daily migration patterns of T cells in well-nourished organisms and are elevated in the malnourished. We examined the effect of malnutrition on T cell migration by comparing the migration patterns of adoptively transferred malnourished and control T cells in the lymphoid organs of malnourished and control recipients. We found that malnourished T cells generally entered lymphoid tissues more efficiently than control T cells, regardless of recipient. Strikingly, the bone marrow of malnourished recipients attracted naïve malnourished T cells, but not control T cells, more efficiently than control bone marrow. In contrast, the spleens of malnourished and control mice attracted similar numbers of naïve T cells. Further experiments revealed that T cells residing in the bone marrow of malnourished mice express higher levels of CCR7 and lower levels of CD11a than control T cells. We also examined the effect of T cell-specific deficiency of the glucocorticoid receptor on T cell migration to the bone marrow in malnourished mice. Indeed, similarly low percentages of glucocorticoid receptor deficient T cells were observed in the bone marrow of malnourished and control mice, indicating that T cell expression of the glucocorticoid receptor is required for T cell migration to the bone marrow. Overall, we have determined that malnutrition modifies both the bone marrow and naïve T cells to promote naïve T cell migration to the bone marrow and that at least the T cell-specific effects are mediated via the glucocorticoid receptor. NSF-MRI [DBI- 1920116] NSF-RUI [IOS-1951881] 

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4. Distinct lymph node entry efficiencies for CD8+ and CD4+ T cells are eliminated during malnourishment.

   https://doi.org/10.4049/jimmunol.206.Supp.11.17  

   Bowman, Lauren A; Goulmamine, Syreen; Gibson, David; Little, Amie; Bupp, Melanie Gubbels (May 2021, The Journal of Immunology)

   Abstract Previous work suggests that glucocorticoids upregulate expression of CD127, an IL-7 receptor component, on peripheral naïve T cells (NT), even though the total number of peripheral NT declines dramatically during malnourishment. We proposed that CD127 up-regulation contributes to peripheral NT reduction by increasing the scavenge rate of IL-7, providing a mechanism to rapidly adjust the total number of NTs during malnutrition. Each malnourished NT would then receive a larger dose of IL-7 than control NTs. We next wondered if this larger dose might confer additional energy-saving behaviors. NT migration across HEV’s may be a high energy-consuming activity. Thus, we compared lymph node entry rates of adoptively-transferred malnourished and control NT in malnourished and control recipients. Control CD4+ NTs migrated more efficiently than control CD8+ NT, but malnourished CD4+ and CD8+ NT migrated at equivalent rates, regardless of recipient diet. We next analyzed expression of proteins known to be involved in NT migration to uncover the currently unknown mechanisms responsible for these various migration patterns. Flow cytometry analysis revealed malnutrition significantly reduces expression of both components of LFA-1 (CD18 and CD11a), CD49d (a VLA-4 component), and S1PR1 in CD4+ and CD8+ NT. We also compared expression levels of ICAM-1 (CD54), a protein expressed in HEV’s which binds to LFA-1 on migrating NT, in malnourished and control lymph node tissue via confocal microscopy. Improved understanding of altered migration molecule expression during malnourishment should enhance our knowledge of the energy-conserving behavior of NT, as well as uncover strategies to improve vaccination responses in malnourished children. 

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5. 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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