IL-7Rα on CD4+ T cells is required for their survival and the pathogenesis of experimental autoimmune encephalomyelitis

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 t...

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Published in:	Journal of neuroinflammation Vol. 21; no. 1; pp. 253 - 15
Main Authors:	Azizi, Gholamreza, Van den Broek, Bram, Ishikawa, Larissa Lumi Watanabe, Naziri, Hamed, Yazdani, Reza, Zhang, Guang-Xian, Ciric, Bogoljub, Rostami, Abdolmohamad
Format:	Journal Article
Language:	English
Published:	London BioMed Central 08.10.2024 BMC
Subjects:	Animals Biomedical and Life Sciences Biomedicine CD4+ T cell CD4-Positive T-Lymphocytes - immunology CD4-Positive T-Lymphocytes - metabolism Cell Survival - drug effects Cell Survival - physiology Cytokines - metabolism Encephalomyelitis, Autoimmune, Experimental - chemically induced Encephalomyelitis, Autoimmune, Experimental - genetics Encephalomyelitis, Autoimmune, Experimental - immunology Encephalomyelitis, Autoimmune, Experimental - metabolism Encephalomyelitis, Autoimmune, Experimental - pathology Experimental autoimmune encephalomyelitis IL-7 receptor alpha Immunology Mice Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Multiple sclerosis Myelin-Oligodendrocyte Glycoprotein - immunology Myelin-Oligodendrocyte Glycoprotein - toxicity Neurobiology Neurology Neurosciences Peptide Fragments - immunology Peptide Fragments - metabolism Peptide Fragments - toxicity Receptors, Interleukin-7 - genetics Receptors, Interleukin-7 - metabolism Experimental autoimmune encephalomyelitis Multiple sclerosis CD4 IL-7 receptor alpha T cell CD4+ T cell
ISSN:	1742-2094, 1742-2094
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Summary:	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 Il7ra fl/fl /CD4CreER T2 double transgenic mouse line (henceforth CD4 Δ Il7ra ), susceptible to tamoxifen-induced knockout of the IL-7Rα gene in CD4 + T cells. CD4 Δ Il7ra mice were immunized with MOG 35 − 55 for EAE induction and monitored for disease development. The expression of IL-7Rα, CD4 + T cell numbers, and MOG 35 − 55 -specific CD4 + T cell response was evaluated in the central nervous system (CNS) and lymphoid tissues by flow cytometry. Additionally, splenocytes of CD4 Δ Il7ra mice were stimulated with MOG 35 − 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 CD4 Δ Il7ra 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 CD4 Δ Il7ra mice, followed by slow repopulation up to the initial numbers. CD4 Δ Il7ra 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 CD4 Δ Il7ra mice. Tracking MOG 35 − 55 -specific CD4 + T cells revealed a significant reduction in their numbers in CD4 Δ Il7ra mice and decreased proliferation and cytokine production in response to MOG 35 − 55 . Conclusion Our study demonstrates that IL-7Rα on peripheral CD4 + T cells is essential for their maintenance, immune response, and EAE pathogenesis.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1742-2094 1742-2094
DOI:	10.1186/s12974-024-03224-2