T cell costimulatory receptor 4-1BB and human anti-viral immunity.
Published: 2004
Language: eng
Number of pages: 161
Description: Further analysis focused on human Influenza- and EBV-specific memory cytotoxic lymphocytes. Responses to 4-1BB costimulation were analyzed in a novel antigen presenting system, utilizing autologous monocytes as antigen presenting cells, with costimulatory molecules delivered via recombinant adenoviruses. 4-1BB costimulation had an adjuvant effect on the expansion and effector function of Influenza and EBV-specific cytotoxic CD8 T cells. 4-1BB costimulation expanded memory T cells with faster kinetics than B7.1 costimulation and yielded more mature CD27- effector T cells under some conditions. Surprisingly, no benefit was observed by combining 4-1BBL and B7 costimulation, suggesting strong costimulatory signals might inhibit responses.For complete activation, T cells require antigen specific and costimulatory signals. While CD28 is the best-known costimulatory molecule, other costimulatory molecules have recently been characterized. 4-1BB, a member of the TNF-receptor family, is an important costimulatory molecule expressed after T cell activation. The role and function of 4-1BB in human T cell responses is characterized herein. With age, inflammatory conditions, or in chronic diseases, humans accumulate CD28- T cells. To determine whether 4-1BBL can activate human CD28-T cells, 4-1BBL costimulatory signals were combined with anti-TCR signaling in a polyclonal activation system. Human CD28- T cells responded to 4-1BB costimulation by proliferation, acquisition of effector function, enhancement in cytotoxicity and upregulation of survival factors.HIV-specific responses in early and chronic HIV patients were analyzed in the system described above. As shown for healthy donors, 4-1BBL enhanced the proliferation and effector function of HIV-specific cytotoxic T cells. When both 4-1BBL and B7.1 costimulation was utilized, surprising differences were uncovered between early and chronic HIV patients. Patients at the early stages of infection did not show a benefit when 4-1BBL and B7.1 were combined, while chronic patients showed an additive or synergistic effect. These results suggest that HIV-specific cytotoxic T cells in chronic infection are less responsive to activating signals and thus require stronger costimulatory signals for activation. As the goal of many vaccines is to generate efficient, long-lived memory T cells, inclusion of costimulatory molecules might be of benefit in HIV therapeutic vaccines.
Notes: Adviser: Tania Watts.

Thesis (Ph.D.)--University of Toronto, 2004.

Electronic version licensed for access by U. of T. users.

Source: Dissertation Abstracts International, Volume: 65-10, Section: B, page: 5056.