Proposed mechanism by which constitutive, T-cell–restricted T-bet overexpression causes maturational arrest of mononuclear phagocyte lineage cells and secondary PAP. Transgenic mice overexpressing T-bet in T lymphocytes from the human CD2 promoter exhibit constitutive IFNγ expression and multiple primary and secondary downstream biological consequences. A critical primary effect (black arrow) is activation of CD4⁺ T cells and promotion of T_H1 cell differentiation resulting in T_H1 cell accumulation and activation. Secondary consequences (gray arrows) include lymphocytic infiltration of the lungs and tissues, marked accumulation of pulmonary alveolar macrophages, maturational arrest of mononuclear phagocytic lineage cells, and time-dependent accumulation of pulmonary surfactant in alveolar macrophages/alveoli (secondary PAP). Characteristics of the alveolar macrophages (large, foamy-appearing, CD11b^HiCD11c⁺, reduced phagocytosis, reduced PPARγ, and ABCG1 messenger RNA [mRNA]) were similar to those of mice and humans with PAP caused by the disruption of GM-CSF signaling, yet GM-CSF mRNA was increased in the lungs of transgenic mice. Pulmonary MCP-1 was also increased (as it is in PAP, caused by the disruption of GM-CSF signaling) and likely contributed to mononuclear phagocyte recruitment (open arrows). Together, these results suggest that secondary PAP occurring in the context of increased expression of T-bet in T cells may be caused by an interruption of the GM-CSF-PU.1-PPARγ-ABCG1 axis, which is critical to surfactant clearance by alveolar macrophages but downstream of PU.1. However, the precise mechanism by which this signaling axis is disrupted in alveolar macrophages and the signaling molecule(s) responsible remain to be determined.