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 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^ΔIl7ra), susceptible to tamoxifen-induced knockout of the IL-7Rα gene in CD4⁺ T cells. CD4^ΔIl7ra 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^ΔIl7ra 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^ΔIl7ra 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^ΔIl7ra mice, followed by slow repopulation up to the initial numbers. CD4^ΔIl7ra 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^ΔIl7ra mice. Tracking MOG_35 - 55-specific CD4⁺ T cells revealed a significant reduction in their numbers in CD4^ΔIl7ra 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.