Alveolarization in retinoic acid receptor-beta-deficient mice.

Retinoids bind to nuclear receptors [retinoic acid receptors (RARs) and retinoid X receptors]. RARbeta, one of three isoforms of RARs (alpha, beta, and gamma), is expressed in the fetal and adult lung. We hypothesized that RARbeta plays a role in alveolarization. Using morphometric analysis, we determined that there was a significant increase in the volume density of airspace in the alveolar region of the lung at 28, 42, and 56 d postnatal age in RARbeta null mice when compared with wild-type controls. The mean cord length of the respiratory airspaces was increased in RARbeta null animals at 42 d postnatal age. Respiratory gas-exchange surface area per unit lung volume was significantly decreased in RARbeta null animals at 28, 42, and 56 d postnatal age. In addition, alveolar ducts tended to comprise a greater proportion of the lung airspaces in the RARbeta null mice. The RARbeta null mice also had impaired respiratory function when compared with wild-type control mice. There was no effect of RARbeta gene deletion on lung platelet-derived growth factor (PDGF) receptor alpha mRNA levels in postnatal lung tissue at several postnatal ages. However PDGF-A protein levels were significantly lower in the RARbeta null mice than in wild-type controls. Thus, deletion of the RARbeta gene impairs the formation of the distal airspaces during the postnatal phase of lung maturation in mice via a pathway that may involve PDGF-A.

Absence of gamma-interferon-inducible lysosomal thiol reductase in melanomas disrupts T cell recognition of select immunodominant epitopes.

Long-lasting tumor immunity requires functional mobilization of CD8+ and CD4+ T lymphocytes. CD4+ T cell activation is enhanced by presentation of shed tumor antigens by professional antigen-presenting cells (APCs), coupled with display of similar antigenic epitopes by major histocompatibility complex class II on malignant cells. APCs readily processed and presented several self-antigens, yet T cell responses to these proteins were absent or reduced in the context of class II+ melanomas. T cell recognition of select exogenous and endogenous epitopes was dependent on tumor cell expression of gamma-interferon-inducible lysosomal thiol reductase (GILT). The absence of GILT in melanomas altered antigen processing and the hierarchy of immunodominant epitope presentation. Mass spectral analysis also revealed GILT's ability to reduce cysteinylated epitopes. Such disparities in the profile of antigenic epitopes displayed by tumors and bystander APCs may contribute to tumor cell survival in the face of immunological defenses.