Immune responses to antigens presented at skin, or other epithelial surfaces such as the cervix, are important for the clearance of viral infections, such as human papillomavirus (HPV) that infect epithelial cells [13]. Elucidation of the components of an effective immune response to antigens presented in this manner will potentially aid in design of immune modulatory techniques or therapeutic vaccine strategies to treat conditions such as cervical cancer. This thesis addresses the role of CD4+ T lymphocytes in immune responses to antigens presented in skin. CD4+ T cells have a well established role in the priming of CD8+ T cells, such that priming without help results in defective CD8+ T cell memory response [15]. The role of CD4+ T cells in the immune response subsequent to priming is less well delineated [15, 16]. Murine skin grafting is a model of antigen presented at an epithelial surface. The model used in this thesis utilises grafts transgenically expressing neo-antigens (human growth hormone=hGH, ovalbumin=OVA) under the control of a keratin promoter (K14 or K5) in the graft. The corresponding mice are termed K14hGH and K5mOVA. With hGH as the antigen, rejection of such skin grafts were shown to require CD4+ T cells [1]. The most surprising finding was that this requirement for CD4+ T cells was maintained even in an antigen-experienced host (in the recall immune response to hGH). CD4+ T cells are required by graft-primed recipients to reject hGH-expressing grafts, but are not required to reject grafts expressing alternative antigens such as OVA. In an adoptive transfer model into lymphopaenic hosts, when high numbers of CD8+ T cells were transferred, any addition of CD4+ T cells was superfluous. However, with low numbers of OVA-specific CD8+ T cells, the addition of CD4+ T cells resulted in a significantly faster rate of K5mOVA skin graft rejection. This helper enhancement of K5mOVA skin graft rejection is maintained, even 7 when CD8+ T cells were previously activated to a memory phenotype prior to transfer, indicating that CD4+ T cells do have effects after CTL priming in vivo. The requirement for CD4+ T cells in the rejection of C57.K14hGH grafts is abrogated by the addition of a local inflammatory stimulus (TLR7 agonist, imiquimod). This is a local rather than systemic effect, suggesting an influence on trafficking or local effector function. Administration of agonist anti-CD40 antibody also partially abrogates the need for CD4+ T cells in rejection of C57.K14hGH grafts by primed hosts. Although CD40 has a well established role in priming of naïve CTL responses, our findings indicate that CD40 can alter events after priming, and suggests a possible mechanism for the role of CD4+ T cells in this system. With these data, we speculate that CD4+ T cells may provide help by altering the state of APC cross-presenting antigen to experienced CD8+ T cells, and that this can be substituted by TLR or CD40 mediated activation of APC. The result may be an increased number of effector CD8+ T cells, as we demonstrate that high numbers of antigen-specific CD8+ T cells can abrogate this effect.
| Identifer | oai:union.ndltd.org:ADTP/290705 |
| Creators | Jennifer Broom |
| Source Sets | Australiasian Digital Theses Program |
| Detected Language | English |
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