Antigen presentation by local macrophages promotes nonallergic airway responses in sensitized mice

Abstract

Local inflammatory responses involve relocating immune functions generated by previous immunization to confined parts of the body, and hence are presumed to reflect the prevailing systemic immune bias. To verify to what extent local antigen-presenting cells (APCs) may modulate immune inflammation, we analyzed the consequences of antigen presentation by macrophages on Th2-dependent airway inflammation in ovalbumin (OVA)-sensitized mice. In contrast to challenge with free OVA, which triggers airway eosinophilia and Th2 cell recruitment, intratracheal instillation of immortalized spleen macrophages (Mf4/4 cells), pulsed with OVA, promoted a nonallergic airway response featuring recruitment of interferon-gamma-producing Th1 cells. Combining OVA-Mf4/4 instillation with OVA inhalation strongly reduced airway eosinophilia. Inflammation repression persisted after secondary OVA challenge and depended on the antigen-presenting ability of the macrophages. Arguing against Th1-mediated counter-regulation, Th1/Th2 ratios remained unaltered in macrophage-treated/OVA-challenged mice. In contrast, levels of interleukin-4 and interleukin-13 mRNA in lung tissue CD4+ T cells were strongly downregulated, indicating a suppression of Th2 cell activation. These results document a role for local macrophages/APCs in controlling the nature and intensity of local immune inflammatory responses. The resulting segregation of systemic and local levels of immune reactivity may enable local inflammation tolerance; it is a nonallergic airway response despite systemic sensitization.