Direct recognition of tumors by regulatory T-cells with suppression of immune rejection.

regulatory T-cell;immune rejection;suppression;antigen specificity;Immunology

Moake, Matthew MorganSchneck, Jonathan P. ;

Johns Hopkins University

关键词: regulatory T-cell;    immune rejection;    suppression;    antigen specificity;    Immunology;   

Others  :  https://jscholarship.library.jhu.edu/bitstream/handle/1774.2/36987/MOAKE-DISSERTATION-2014.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: JOHNS HOPKINS DSpace Repository

【 摘 要 】

It is well established that the process of tumor progression is recognized by the immune system, and that cancer cells actively manipulate this system via production of inhibitory cytokines, antigenic loss, and alteration of immune-relevant cell surface molecules such as costimulatory ligands and Major Histocompatability Complex (MHC) II, which is required for CD4+ T-cell recognition.Regulatory T-cells (Tregs) plan an active part in the immune response to cancer.A growing body of literature suggests that Tregs demonstrate improved suppressive capacity when both Treg and effector T-cell (Teff) are specific for antigens within the same target cell, but the mechanisms behind this observation are as of yet unknown.In this study we hypothesized that the upregulation of MHCII by tumor cells allows for direct recognition by Tregs and provides a mechanism for antigen-specific suppression.Using a novel tumor model in which MHCII knockout mice were challenged with an MHCII-inducible, ovalbumin (OVA)-expressing B16 melanoma, we were able to demonstrate antigen-specific treatment with OVA-specific OTI CD8+ T-cells that was subsequently suppressed by OVA-specific OTII Tregs.Through bioluminescent imaging (BLI), histology, and ex vivo flow cytometry, we were able to demonstrate that our OTI cells proliferated, matured, trafficked to and accumulated within the tumor, and developed an effector phenotype consisting of IFNγ and TNFα cytokine production and efficient lysis of antigen-loaded targets.To expand upon our suppression findings, we developed a panel of OVA-expressing B16 tumors with variable expression levels of MHCII and evaluated their ability to induce Treg suppression.Unfortunately, we were unable to demonstrate suppression of tumor rejection or alteration in OTI phenotype by our Tregs, and subsequently determined that, through an unknown mechanism, our OVA-expressing B16 tumors were unable to present OVA to OTII T-cells, thus nullifying our Treg studies.Although ultimately disappointing, the tumor model, B16 variants, and experimental framework generated here will serve as useful tools for the future analysis of direct antigen presentation by tumors.Thesis Advisor:Dr. Hyam LevitskySecond Reader:Dr. Ivan Borrello