Glucocorticoids redirect naïve T cells to the bone marrow for preservation in malnourished mice 2253552

Abstract

Abstract Introduction Malnutrition impairs immunity and contributes significantly to child mortality. This depressed immunity involves the impairment of T cells. During malnutrition, effector T cells experience a decline in number, proliferative capacity, and cytokine secretion. As little is known about changes involving naïve T cells, we conducted a study to assess the impact of malnutrition on the naïve T cell population. Methods B6, B6 Thy1.1, and Nr3clfl/fl CD4.cre + (conditional glucocorticoid receptor knockout/cGRKO) mice were randomly assigned to an ad libitum (AL) or a malnutrition (MAL) diet. After one week of MAL, cells were isolated from the femoral bone marrow (BM) and axillary, brachial, and inguinal lymph nodes (LN). Flow cytometry was used to identify naïve (CD44lo) T cells and assess apoptosis. In an adoptive transfer experiment, cells from AL Thy1.1+ and MAL Thy1.1- donor mice were labeled and retro-orbitally injected into AL Thy1.1- and MAL Thy1.1- recipients. Recipients were euthanized two hours after injection, and percent change in the AL: MAL naïve T cell ratio was calculated. Cells from the spleen and BM of MAL and AL cGRKO mice were stained with anti- CD44, CD62L, CD4, CD8, CXCR4, and CCR7 and acquired by flow cytometry. Results The number of naïve T cells decreased in LN and increased in BM during MAL, and MAL naïve T cells in BM were less apoptotic than controls. MAL naïve CD4+ T cells preferentially migrated to BM while AL control cells preferentially migrated to LN in a T cell-intrinsic fashion. T cell-specific lack of the glucocorticoid receptor greatly reduced the number of naïve T cells in BM of MAL mice. T cell sensitivity to glucocorticoids was also required for naïve CD4+ T cells’ elevated expression of CXCR4 in the spleen and CCR7 in BM during MAL. Conclusion These findings suggest that naïve T cell migration to BM during MAL is intrinsic and requires sensitivity to glucocorticoid. This phenomenon is likely adaptive and intended to preserve naïve T cells during malnutrition. Funding Source National Science Foundation grant numbers (1951881) and (1920116) awarded to M.R. Gubbels Bupp Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)