Investigating Th1 Cell Positioning and Cross-Regulation with IL-4 in Immune Defense 2257324

Abstract Introduction Leishmania major (L.major) is an intracellular parasite that causes cutaneous leishmaniasis, a disease in which the balance between the response of Th1(protective) and Th2 (suppressive) determines the outcome of infection. While Th1-derived interferon-γ (IFN-γ) activates infected phagocytes, Th2-derived interleukin-4 (IL-4) suppresses Th1 activity and aggravates parasite persistence. The way in which IL-4 shapes the spatial organization and dynamics of effector T cells within inflamed tissue, however, remains enigmatic. Methods In this study we employed the OVA/CFA model, where CXCL10-rich immune-niches that optimize Th1 activation have been well described, as a mechanistic proxy for L. major infection to examine how IL-4 shapes Th1 motility and niche organization. Results Neutralizing IL-4 prior to immune-cluster formation markedly increased T-cell motility, did not alter CXCL10 expression, and was associated with more dispersed and less confined immune aggregates. In contrast, blocking IL-4 after niches had formed reduced T-cell motility and converted the clusters into large chemokine-dense hubs. Conclusion These findings reveal that IL-4 may exert distinct, phase-specific control over tissue immunity. Early IL-4 confines emerging immune niches and limits Th1 movement, while late IL-4 disperses established niches and contributes to immune resolution. Together, these findings identify IL-4 as a dynamic regulator of spatial immune architecture and provide a framework for understanding how IL-4 shapes Th1 positioning and cross-regulation during L. major infection. This offers insights that may guide new strategies to enhance protective immunity against parasitic infections. Funding Source n/a Topic Categories Cellular Adhesion, Migration, and Inflammation (CAM)