Antigen-specific memory T cell distribution in non-lymphoid tissue

Thesis (S.M.)--Massachusetts Institute of Technology, Biological Engineering Division, 2007.Includes bibliographical references (leaves 28-34).CD8+ T cells are the main adaptive immune system cell type responding to intracellular pathogens, particularly viruses, and tumor antigens. In the case of influenza, activated T cells migrate from the mediastinal (draining) lymph nodes to the lung where they perform their cytolytic function. After pathogen clearance, memory CD8+ T cells are generated, giving rise to long-term protection from reinfection. However, these cells are no longer detectable in the lung parenchyma six months post-infection, and cell-mediated immunity, and protection is lost. Knock-out studies in mice show that interleukin 15 (IL-15) is essential for memory CD8+ T cell proliferation. Fibroblasts, macrophages, dendritic cells and epithelial cells express IL-15 and its receptor isoform [alpha] (IL-15R[alpha]). Histological studies suggest that memory CD8+ T cells preferentially reside in peribronchiolar and perivascular areas, the stroma, of the lung. We hypothesize that memory CD8+ T cells preferentially reside in regions where molecules necessary for their maintenance, for example, IL-15/R secreting cells, are located. In this study, we have shown that antigen-specific 2C GFP effector memory CD8+ T cells are generated in B6 recipient mice 30-32 days after influenza virus infection, preferentially reside in peribronchiolar areas. Both 2C and 2C GFP recipient mice have severe vasculitis and widely distributed inflammatory infiltrates 7 days post-infection. Lower lung lobes appear to be more affected than upper lobes at this time point. On day 30, most of the airways have been cleared and restored. Although lymphoid-appearing nodules were detected in the lungs 31 dpi, no clusters of B cells and T cells suggesting induced BALT were identified by immunofluorescence.(cont.) Interestingly, antigen-specific GFP cells preferentially remained in the lung tissue and were almost undetectable in spleens, lymph nodes, and livers. This preference was not observed in 2C (non-GFP) recipient mice. Immunofluorescence studies showed no colocalization between 2C GFP T cells and dendritic cells that might suggest stable dendritic cell interactions contribute to antigen-specific cells preferentially residing in the lung stroma. Further studies are necessary to determine what other cell types might contribute to this phenomenon. These results provide some insight into how structural elements in non-lymphoid tissue influence cell-mediated immunity.by Mobolaji O. Olurinde.S.M

Factors contributing to T cell persistence in a tolerizing tumor environment

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2010.Cataloged from PDF version of thesis.Includes bibliographical references.Cancer is a leading cause of death worldwide, accounting for at least 10% of all deaths globally. Current therapies for cancer include surgical excision, chemotherapy and immunotherapy. CD8[+] T cells are adaptive immune cells responsible for eradicating tumor cells. However, these T cells can be rendered ineffective through tolerance. Yet in various mouse models and human patients, tolerant T cells persist. The aim of this project is to identify factors that support T cell persistence in a tolerizing tumor environment. Using a spontaneous prostate cancer model, we study antigen-specific T cells that have been shown to be locally tolerant in the prostate tumor environment. In this thesis, I compare the immune response in normal, antigen bearing, tumor transgenic and tumor-antigen transgenic mouse models. Results show that T cell infiltration and persistence in the tolerizing prostate environment is dependent on the presence of antigen and tumorigenic/tumor-related factors. Although antigen-specific T cells are locally tolerant in the prostate of tumor-antigen transgenic mice, they generally persist in the prostates of tumor transgenic mice regardless of whether antigen is present or not. Further analyses revealed that T cells infiltrate the prostate and can proliferate extensively in the tolerizing tumor environment due to the presence of antigen. Interestingly, antigen-specific T cells are depleted from the spleens of mice that express antigen in their prostates.(cont.) This depletion from the spleen is correlated with low levels of IL-7R[alpha] expression and the presence of antigen in the prostate. Tumorigenic or tumor-related factors in the prostate also appear to be supporting CD8[+] T cell persistence. This thesis shows that persistence of antigen-specific T cells in the tumor environment is not dependent on IL-15 and IL-7; cytokines known to support proliferation and maintenance of persisting functional CD8[+] T cells. Some potential candidates are also discussed. More investigative work needs to be done to identify the role of these factors on T cell infiltration and persistence. In combination with tolerance-breaking strategies, persisting T cells may be excellent vehicles for delivering site-specific cancer immunotherapy.by Mobolaji 0. Olurinde.Ph.D