Biology of human T cell activation [electronic resource].

Maus, Marcela Valderrama.
167 p.
Local subjects:
Penn dissertations -- Cell and molecular biology.
Cell and molecular biology -- Penn dissertations.
System Details:
Mode of access: World Wide Web.
Adoptive immunotherapy has great potential to treat a wide variety of diseases, including cancer and infectious diseases, but it requires ex vivo activation and expansion of human T lymphocytes. The research described here used artificial antigen presenting cells (aAPCs) designed to test the requirements for activation and expansion of human CD4+ and CD8+ T lymphocytes. First, we have focused on the co-stimulatory requirements of CD4+ and CD8+ T cells in polyclonal populations. Although CD4+ T cells require only TCR/CD3 and CD28 stimulation for long-term growth, we have found this to be insufficient for the long-term growth of CD8+ T cells. To overcome the difficulty in expanding CD8+ cytotoxic T lymphocytes (CTLs), we have developed cell-based aAPCs expressing the co-stimulatory molecule 4-1BB ligand in addition to surface coating with anti-CD3 and anti-CD28 antibodies. These aAPCs activate and rapidly expand purified CD8+ T cells from any donor. This system can be used to expand very limited numbers of antigen-specific CTL to numbers suitable for use in immunotherapy within five weeks of ex vivo culture. However, further studies revealed that the engineered cellular aAPCs are likely to provide costimulation beyond the TCR, CD28, and 4-1BB, as bead-based aAPCs coated with the same combination of co-stimulatory molecules were unable to stimulate the long-term expansion of CD8+ T cells. Because successful applications of adoptive immunotherapy will likely require infusions of CD4+ T cells in addition to CTLs, we have also developed antigen-specific aAPC systems for CD4 + T cells, using magnetic beads coated with MHC-peptide complexes as aAPCs. We have found that beads coated with MHC-peptide complexes and anti-CD28 support the long-term growth of antigen-specific CD4+ T cells at least as well as autologous dendritic cells pulsed with peptide, and that no further co-stimulation is required. The CD4+ T cells remain functional and have a Th1 cytokine profile, but maintain the ability to produce the Th2-type cytokine IL-4. Furthermore, antigen-specific aAPCs promote the enrichment of antigen-specific T cells. Thus, artificial APCs provide both a defined system in which to study T cell activation and are proving to be useful in the clinical setting.
Thesis (Ph.D. in Cell and Molecular Biology) -- University of Pennsylvania, 2003.
Source: Dissertation Abstracts International, Volume: 64-04, Section: B, page: 1676.
Supervisor: Carl H. June.
Local notes:
School code: 0175.
June, Carl H., advisor
University of Pennsylvania.
Contained In:
Dissertation Abstracts International 64-04B.
Access Restriction:
Restricted for use by site license.
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