Early TNFα signaling promotes classical activation of dendritic cells in lung associated lymph nodes to prime development of protective immunity against cryptococcal infection

Abstract

Abstract Cryptococcus neoformans is a common opportunistic pathogen that requires intact T cell-mediated immunity for protective host defenses. While Th1/Th17 responses contribute to the effective containment and elimination of C. neoformans, Th2 responses are non-protective and can worsen clearance outcomes. Previous studies showed that early tumor necrosis factor alpha (TNFα) signaling is required for optimal clearance, while its absence leads to immune dysregulation and persistent fungal infection. To determine mechanism(s) of early TNFα signaling in the generation of protective anti-cryptococcal immunity, we evaluated the contribution of TNFα to the priming of the innate immune system for optimal T-cell development. In CBA/J mice depleted of TNFα at the time of infection with C. neoformans, we evaluated DC accumulation, activation profile, and interaction frequencies with T cells in lung associated lymph nodes (LALN) in comparison with the infected control mice. We found that early TNFα depletion during pulmonary C. neoformans infection resulted in: 1) lack of pulmonary fungal clearance and enhanced dissemination; 2) decreased Th1/Th17 polarization and CD4+ T cell activation in the LALN; 3) diminished DC accumulation in the LALN; 4) decreased expression of classical activation DC signatures (co-stimulatory molecules CD40 and CD86), pro-Th1 and pro-Th17 cytokines (IL-12b, TNFα, IL-23a and IL-21); and 5) increased expression of the alternative activation DC signatures (Fizz and Gal3) and pro-Th2 cytokines (IL4 and IL-10). Thus, our data indicates early TNFα signaling promotes classical activation of DC in lung associated lymph nodes thereby priming development of protective immunity against cryptococcal infection.