IL-4Rα mediated signalling on Foxp3+ T regulatory cells has a protective role during cutaneous Leishmaniasis 2258800

Introduction Forkhead box P3 (Foxp3+) T regulatory (Treg) cells are a unique subset of CD4+ T cells that play important immunomodulatory roles, maintaining a balance between Type 1 and Type 2 immune responses. During L. major-induced cutaneous leishmaniasis, Treg cells accumulation at the site of infection has been implicated in suppressing a detrimental Type 2 immune response by modulating early interleukin (IL)-4 production; however, it remains unclear if IL-4Rα mediated signalling on Treg cells plays a significant role in this process. Methods To investigate this further, a BALB/c model was utilized in which IL-4Rα chain was selectively knocked down on Treg cells (Foxp3creIL-4Rα-/lox mice). Results Foxp3creIL-4Rα-/lox male mice, which had a greater degree of IL-4Rα knockdown on Foxp3+ Treg cells (≈ 102%), developed significant footpad swelling and ear swellings and increased parasitic burdens. The hypersusceptible phenotype observed in Foxp3creIL-4Rα-/lox BALB/c male mice was associated with an amplified Type 2 immune response and increased Treg cell recruitment. Flow cytometry analysis revealed that depletion of IL-4Rα on Foxp3+ Treg cells resulted in the induction of a L. major-induced Indoleamine 2,3 dioxygenase (IDO) mechanism that facilitated Leishmania replication. Conclusion Collectively, these data suggest a protective role for IL-4Rα mediated signalling on Treg cells in suppressing a detrimental Type 2 immune response during cutaneous Leishmaniasis.