The Tbx21 gene encodes a transcription factor that controls expression of interferon-gamma and is involved in Th1 cell lineage development. Mice that are homozygous for this targeted mutation of Tbx21, in which a NEO cassette replaces 2 Kb of sequence (exon 1 and flanking sequence), are viable and fertile. No gene product (mRNA or protein) is detected in isolated lymph node T-cells by Northern or Western blot analysis. T cells from the homozygotes do not produce the TH1 type cytokine, interferon-gamma, and secrete elevated levels of TH2 type cytokines in vitro to TCR cross-linking and in vivo to protein antigen immunization. Additionally, mice homozygous for the targeted mutation on the BALB/c genetic background are susceptible to Leishmania major infections. Without induced sensitization or challenge, female homozygotes display airway hyper responsiveness (AHR) with resulting airway remodeling similar to characteristics of asthma. Histological analysis of lung from female homozygous mice, aged 4 to 6 weeks, reveals eosinophil and lymphocyte infiltration of peribronchial and perivenular tissue, thickening of the subepithelial collagen layer, and increased numbers of myofibroblast cells in bronchial tissue. Bronchial alveolar lavage fluid contains elevated levels of TGF-beta1, TNF-alpha, IL-4 and IL-13. Mice heterozygous for the targeted mutation display an intermediate phenotype. Homozygous male mice, at 8 weeks to 28 weeks of age, weigh more than wildtype controls. Although food intake on a low fat diet was similar for all genotypes, homozygous mice exhibit a lower food intake on a high fat diet compare to wildtype controls. Homozygotes also display increased intra-abdominal or visceral adipose tissue mass and increased adipocyte size when compared to controls. Homozygotes at 8 weeks and 6 months of age exhibit lower fasting and fed serum insulin levels, better glucose tolerance and enhanced insulin sensitivity than wildtype controls. Adipose tissue in homozygotes have fewer CD45+, CD4+, CD8+, and NK cells and reduced cytokine secretion.
