Loci controlling lymphocyte production of interferon gamma after alloantigen stimulation in vitro and their co-localization with genes controlling lymphocyte infiltration of tumors and tumor susceptibility

Low infiltration of lymphocytes into cancers is associated with poor prognosis, but the reasons why some patients exhibit a low and others a high infiltration of tumors are unknown. Previously we mapped four loci (Lynf1–Lynf4) controlling lymphocyte infiltration of mouse lung tumors. These loci do not encode any of the molecules that are involved in traffic of lymphocytes. Here we report a genetic relationship between these loci and the control of production of IFNγ in allogeneic mixed lymphocyte cultures (MLC). We found that IFNγ production by lymphocytes of O20/A mice is lower than by lymphocytes of OcB-9/Dem mice (both H2(pz)) stimulated in MLC by irradiated splenocytes of C57BL/10SnPh (H2(b)) or BALB/cHeA (H2(d)) mice, or by ConA. IFNγ production in MLCs of individual (O20 × OcB-9)F(2) mice stimulated by irradiated C57BL/10 splenocytes and genotyped for microsatellite markers revealed four IFNγ-controlling loci (Cypr4-Cypr7), each of which is closely linked with one of the four Lynf loci and with a cluster of susceptibility genes for different tumors. This suggests that inherited differences in certain lymphocyte responses may modify their propensity to infiltrate tumors and their capacity to affect tumor growth

Genetic Regulation of T Regulatory, CD4, and CD8 Cell Numbers by the Arthritis Severity Loci Cia5a, Cia5d, and the MHC/Cia1 in the Rat

T cells have a central role in the pathogenesis of autoimmune arthritis, and several abnormalities in T cell homeostasis have been described in rheumatoid arthritis (RA). We hypothesized that T cell phenotypes, including frequencies of different subsets of T regulatory (Treg) cells and in vitro functional responses could be genetically determined. Furthermore, we considered that the genetic contribution would be accounted for by one of the arthritis regulatory quantitative trait loci (QTL), thus providing novel clues to gene mode of action. T cells were isolated from thymus, peripheral blood, and spleen from DA (arthritis-susceptible) and ACI and F344 (arthritis-resistant) strains and from F344.DA(Cia1), DA.F344(Cia5a), and DA.F344(Cia5d) rats congenic for arthritis QTL. T cell subpopulations differed significantly between DA, F344, and ACI. DA rats had an increased frequency of CD4+ cells, and a reduction in CD8+ and CD4+CD45RC|o Treg cells, compared with F344. The differences in CD4/CD8 and CD4+CD45RC|o Treg cells were accounted for by Cia5a. DA rats also had a reduced frequency of CD8+CD45RC|o CD25+ Treg cells compared with F344, and that difference was explained by Cia5d. DA rats also had a significantly lower frequency of CD4+CD25+ and CD8+CD25+ thymocytes, and of peripheral blood CD8+CD45RC|o Treg cells, compared with F344 rats, and that difference was accounted for by the MHC. This is the first identification of arthritis severity QTL regulating numbers of CD4+CD45RC|o (Cia5a) and CD8+CD45RC|o CD25+ (Cia5d) Treg cells. The MHC effect on CD8+ Treg cells and CD25+ thymocytes raises a novel potential explanation for its association with arthritis

Stem cells and corneal epithelial maintenance:insights from the mouse and other animal models

Maintenance of the corneal epithelium is essential for vision and is a dynamic process incorporating constant cell production, movement and loss. Although cell-based therapies involving the transplantation of putative stem cells are well advanced for the treatment of human corneal defects, the scientific understanding of these interventions is poor. No definitive marker that discriminates stem cells that maintain the corneal epithelium from the surrounding tissue has been discovered and the identity of these elusive cells is, therefore, hotly debated. The key elements of corneal epithelial maintenance have long been recognised but it is still not known how this dynamic balance is co-ordinated during normal homeostasis to ensure the corneal epithelium is maintained at a uniform thickness. Most indirect experimental evidence supports the limbal epithelial stem cell (LESC) hypothesis, which proposes that the adult corneal epithelium is maintained by stem cells located in the limbus at the corneal periphery. However, this has been challenged recently by the corneal epithelial stem cell (CESC) hypothesis, which proposes that during normal homeostasis the mouse corneal epithelium is maintained by stem cells located throughout the basal corneal epithelium with LESCs only contributing during wound healing. In this chapter we review experimental studies, mostly based on animal work, that provide insights into how stem cells maintain the normal corneal epithelium and consider the merits of the alternative LESC and CESC hypotheses. Finally, we highlight some recent research on other stem cell systems and consider how this could influence future research directions for identifying the stem cells that maintain the corneal epithelium