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

J Neuroinflammation. 2024 Oct 8;21(1):253. doi: 10.1186/s12974-024-03224-2.

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.

Keywords: CD4+ T cell; Experimental autoimmune encephalomyelitis; IL-7 receptor alpha; Multiple sclerosis.

MeSH terms

  • Animals
  • 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
  • Mice
  • Mice, Inbred C57BL*
  • Mice, Knockout
  • Mice, Transgenic*
  • Myelin-Oligodendrocyte Glycoprotein / immunology
  • Myelin-Oligodendrocyte Glycoprotein / toxicity
  • Peptide Fragments / immunology
  • Peptide Fragments / metabolism
  • Peptide Fragments / toxicity
  • Receptors, Interleukin-7* / genetics
  • Receptors, Interleukin-7* / metabolism

Substances

  • Receptors, Interleukin-7
  • interleukin-7 receptor, alpha chain
  • Myelin-Oligodendrocyte Glycoprotein
  • Peptide Fragments
  • myelin oligodendrocyte glycoprotein (35-55)
  • Cytokines