IL-7Rα on CD4+ T cells is required for their survival and the pathogenesis of experimental autoimmune encephalomyelitis
Gholamreza Azizi, Bram van den Broek, Larissa Lumi Watanabe Ishikawa, Hamed Naziri, Reza Yazdani, Guang‐Xian Zhang, Bogoljub Ćirić, Abdolmohamad Rostami
Abstract
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 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.