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Liver X receptor β is required for the survival of single-positive thymocytes by regulating IL-7Rα expression.

ABSTRACT: Liver X receptors (LXRs) are known as key transcription factors in lipid metabolism and have been reported to play an important role in T-cell proliferation. However, whether LXRs play a role in thymocyte development remains largely unknown. Here, we demonstrated that LXRβ deficiency caused a reduction in single-positive (SP) thymocytes, whereas the transitions from the double-negative to SP stage were normal. Meanwhile, LXRβ-null SP thymocytes exhibited increased apoptosis and impairment of the IL-7Rα-Bcl2 axis. In addition, the LXR agonist T0901317 promoted the survival of SP thymocytes with enhanced IL-7Rα expression in wild-type mice but not in LXRβ-deficient mice. Mechanistically, LXRβ positively regulated the expression of IL-7Rα via direct binding to the Il7r allele in SP thymocytes, and forced expression of IL-7Rα or Bcl2 restored the survival of LXRβ-defective SP thymocytes. Thus, our results indicate that LXRβ functions as an important transcription factor upstream of IL-7Rα to promote the survival of SP thymocytes.

SUBMITTER: Huang H

PROVIDER: S-EPMC8322414 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Liver X receptor β is required for the survival of single-positive thymocytes by regulating IL-7Rα expression.

Huang Huang H Wu Xiaoping X Meng Dongwei D Feng Yizhou Y Zhou Lan L Liu Zhenyu Z Tang Shupei S Li Xueqin X Cao Yi Y He Haiyang H Xie Zhunyi Z Zhang Jingbo J Chen Yongwen Y Zhao Tingting T Wu Yuzhang Y Zhou Xinyuan X

Cellular & molecular immunology 20200922 8

Liver X receptors (LXRs) are known as key transcription factors in lipid metabolism and have been reported to play an important role in T-cell proliferation. However, whether LXRs play a role in thymocyte development remains largely unknown. Here, we demonstrated that LXRβ deficiency caused a reduction in single-positive (SP) thymocytes, whereas the transitions from the double-negative to SP stage were normal. Meanwhile, LXRβ-null SP thymocytes exhibited increased apoptosis and impairment of the ...[more]

PMID: 32963358

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Project description:BackgroundThe IL-7 receptor alpha (IL-7Rα) binds both IL-7 and thymic stromal lymphopoietin (TSLP). IL-7Rα is essential for the development and survival of naive CD4+ T cells and their differentiation to effector/memory CD4+ T cells. Mice lacking IL-7Rα have severe lymphopenia and are resistant to experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis. However, it has been reported that IL-7Rα on peripheral CD4+ T cells is disposable for their maintenance and EAE pathogenesis, which does not align with the body of knowledge on the role of IL-7Rα in the biology of CD4+ T cells. Given that a definitive study on this important topic is lacking, we revisited it using a novel approach, an inducible knockout of the IL-7Rα gene in CD4+ T cells.MethodsWe generated Il7rafl/fl/CD4CreERT2 double transgenic mouse line (henceforth CD4ΔIl7ra), susceptible to tamoxifen-induced knockout of the IL-7Rα gene in CD4+ T cells. CD4ΔIl7ra mice were immunized with MOG35 - 55 for EAE induction and monitored for disease development. The expression of IL-7Rα, CD4+ T cell numbers, and MOG35 - 55-specific CD4+ T cell response was evaluated in the central nervous system (CNS) and lymphoid tissues by flow cytometry. Additionally, splenocytes of CD4ΔIl7ra mice were stimulated with MOG35 - 55 to assess their proliferative response and cytokine production by T helper cells.ResultsLoss of IL-7Rα from the surface of CD4+ T cells in CD4ΔIl7ra mice was virtually complete several days after tamoxifen treatment. The loss of IL-7Rα in CD4+ T cells led to a gradual and substantial decrease in their numbers in both non-immunized and immunized CD4ΔIl7ra mice, followed by slow repopulation up to the initial numbers. CD4ΔIl7ra mice did not develop EAE. We found a decrease in the total numbers of TNF-, IFN-γ-, IL-17 A-, and GM-CSF-producing CD4+ T cells and regulatory T cells in the spleens and CNS of immunized CD4ΔIl7ra mice. Tracking MOG35 - 55-specific CD4+ T cells revealed a significant reduction in their numbers in CD4ΔIl7ra mice and decreased proliferation and cytokine production in response to MOG35 - 55.ConclusionOur study demonstrates that IL-7Rα on peripheral CD4+ T cells is essential for their maintenance, immune response, and EAE pathogenesis.

Dataset Information

Liver X receptor β is required for the survival of single-positive thymocytes by regulating IL-7Rα expression.

Publications

Liver X receptor β is required for the survival of single-positive thymocytes by regulating IL-7Rα expression.

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