Document Type

Article

Publication Date

10-8-2024

Comments

This article is the author's final published version in Journal of Neuroinflammation, Volume 21, Issue 1, 2024, Article number 253.

The published version is available at https://doi.org10.1186/s12974-024-03224-2.

Copyright © The Author(s) 2024

Abstract

BACKGROUND: The 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.

METHODS: We 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.

RESULTS: Loss 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.

CONCLUSION: Our study demonstrates that IL-7Rα on peripheral CD4+ T cells is essential for their maintenance, immune response, and EAE pathogenesis

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Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.

PubMed ID

39380064

Language

English

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