Distinct IL‐7 signaling in recent thymic emigrants versus mature naïve T cells controls T‐cell homeostasis

• Published in: European journal of immunology Vol. 46; no. 7; pp. 1669 - 1680
• Main Authors: Kim, Hye Kyung, Waickman, Adam T., Castro, Ehydel, Flomerfelt, Francis A., Hawk, Nga V., Kapoor, Veena, Telford, William G., Gress, Ronald E.
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 01.07.2016
• Subjects: Animals; Apoptosis - genetics; Apoptosis - immunology; Apoptosis ⋅ Bcl‐2 ⋅ Cytokine ⋅ Proliferation ⋅ STAT5; Cell Movement - immunology; Cell Proliferation; Cell Survival - genetics; Cell Survival - immunology; DNA-Binding Proteins - deficiency; Homeostasis; Immunophenotyping; Interleukin-7 - metabolism; Lymphocyte Activation - immunology; Mice; Mice, Knockout; Mice, Transgenic; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - metabolism; Receptors, Interleukin-7 - metabolism; Signal Transduction; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; Thymus Gland - immunology; Thymus Gland - metabolism; Apoptosis ⋅ Bcl-2 ⋅ Cytokine ⋅ Proliferation ⋅ STAT5
• DOI: 10.1002/eji.201546214
• ISSN: 0014-2980

IL‐7 is essential for T‐cell survival but its availability is limited in vivo. Consequently, all peripheral T cells, including recent thymic emigrants (RTEs) are constantly competing for IL‐7 to survive. RTEs are required to replenish TCR diversity and rejuvenate the peripheral T‐cell pool. However, it remains unknown how RTEs successfully compete with resident mature T cells for IL‐7. Moreover, RTEs express low levels of IL‐7 receptors, presumably rendering them even less competitive. Here, we show that, surprisingly, RTEs are more responsive to IL‐7 than mature naïve T cells as demonstrated by markedly increased STAT5 phosphorylation upon IL‐7 stimulation. Nonetheless, adoptive transfer of RTE cells into lymphopenic host mice resulted in slower IL‐7‐induced homeostatic proliferation and diminished expansion compared to naïve donor T cells. Mechanistically, we found that IL‐7 signaling in RTEs preferentially upregulated expression of Bcl‐2, which is anti‐apoptotic but also anti‐proliferative. In contrast, naïve T cells showed diminished Bcl‐2 induction but greater proliferative response to IL‐7. Collectively, these data indicate that IL‐7 responsiveness in RTE is designed to maximize survival at the expense of reduced proliferation, consistent with RTE serving as a subpopulation of T cells rich in diversity but not in frequency. Both recent thymic emigrant (RTE) and naïve T cells depend on IL‐7 for survival and homeostasis. In RTE cells, IL‐7 strongly induces Bcl‐2 expression to promote cell survival, while in naïve T cells, IL‐7 preferentially promotes proliferation. Thus, distinct IL‐7 response in RTE and naïve T cells maintains both the size and diversity of the peripheral T‐cell pool.