Previous studies employing the generation of MHC-incompatible embryonic chicken chimaeras by injecting MHC-incompatible stem cells resulted in an unexpected finding. Chimaeras made late in gestation developed as adults a severe autoimmune syndrome resembling the human syndrome of Systemic Lupus Erythematosus.
Work in our laboratory aims to understand the role of CD8 T cells in immunity and/or autoimmunity. We have tested a three-cell model of CD4 T cell activation and differentiation during the development of the immune response specific for MHC transplantation antigens in one way mixed lymphocyte reactions. Our model proposes that whether Th1 or Th2 immunity is generated depends on both the ratio of CD4:CD8 T cells specific for antigen at the initiation of the immune response and on the ability of antigens to coordinately induce both CD4 and CD8 T cells.
Previous studies employing parent into F1 models of graft-versus-host disease in mice have shown that the injection of parental cells results in two distinct outcomes. Parental cells which do not have a sufficient number of CD8 T cells present produce an autoimmune syndrome characteristic of systemic lupus erythematosus and a chronic graft-versus-host disease mediated by a Th2 response. Conversely, the presence of an adequate number of CD8 T cells results in a Th1 immune response and acute graft-versus-host disease resulting in the death of the F1 host.
Our findings indicate that the ratio of the number of CD4 T cells to the number of CD8 T cells present in the spleen is crucial in whether naive CD4 T cells differentiate into Th1 or Th2 cells. We refer to this ratio as the CD4:CD8 T cell ratio or CD4:CD8 ratio. Thus, the differentiation of naive CD4+ T cells towards a differentiated Th1 phenotype is critically dependent on the concomitant induction of CD8 T cells by the same antigen, driven by a low CD4:CD8 ratio. In contrast, inefficient induction of CD8 T cells during the initial priming of lymphocytes greatly facilitates the differentiation of CD4 T cells towards the Th2-type lineage, and occurs when the CD4:CD8 ratio is high.
Given our findings on the significance of the ratio of CD4:CD8 T cells in the decision making process of CD4 differentiation stimulated by antigen, we hypothesized that different CD4: CD8 ratios at different stages of development might contribute to the immune response generated at these stages.
We tested this hypothesis in mice by comparing the CD4:CD8 ratio in adults and neonates and the Th1/Th2 responses generated in vitro. This CD4:CD8 T cell ratio is significantly higher in neonates than adults resulting in predominant Th1 responses by adult spleen cells and Th1/Th2 responses by neonatal spleen cells as demonstrated by the ELISPOT assay.
We have compared the CD4:CD8 T cell ratio of a large number of adult and neonatal spleens in several mouse strains and have studied it systematically in BALB/c and C57BL/6 mice by flow-cytometry. We have consistently found a 3-5 fold higher CD4:CD8 T cell ratio in neonates as compared to adults in the strains tested. Furthermore, we found that neonatal spleen cells generate a predominant Th2 response whereas adult spleen cells generate CD4 and CD8 Th1 immunity when activated under the same conditions.
We have further studied the role of CD8 T cells in CD4 T cell differentiation by reconstructing the adult CD4:CD8 T cell ratio in neonatal spleen cells with age-matched, isolated CD8 T cells. We found that in these “CD4:CD8 ratio-reconstructed cultures”, the Th2/IL-4 immunity is suppressed with concomitant generation of Th1/IFN-γ immunity upon activation by allo-antigen. Additionally, we have characterized the phenotype of the T cell mediating Th1/IFNγ immunity in the “CD4:CD8 ratio reconstructed cultures” and we found that while CD8 T cells produce exclusively IFN-γ, CD4 T cells now produce IFN-γ rather than IL-4.
We suggest that physiologically distinct CD4:CD8 ratios at different stages of life should be considered in designing protocols of neonatal vaccination against pathogens that are contained by Th1-type immunity upon infection as adults. Moreover, as elaborated in the discussion, our studies might be pertinent in understanding by which mechanism autoimmunity arises in some cases.
| Identifer | oai:union.ndltd.org:USASK/oai:ecommons.usask.ca:10388/ETD-2015-07-2126 |
| Date | 2015 July 1900 |
| Contributors | Havele, Calliopi |
| Source Sets | University of Saskatchewan Library |
| Language | English |
| Detected Language | English |
| Type | text, thesis |
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