The role of inducible costimulatory molecules in immune responses to infection.
Published: 2006
Language: eng
Number of pages: 187
ISBN-13: 9780494218983
Description: T cells require antigen-specific and costimulatory signals for activation. Here we examined the roles of inducible costimulatory molecules ICOS and 4-1BB in immune responses to infection. We show that ICOS plays a critical role in the control of Salmonella infection in mice, with effects on antibody, Th1, and CD8+ T cell responses. Furthermore, in vitro studies suggest that in vivo effects of ICOS on CD8+ T cells could be direct. We further examined the relationship of ICOS to 4-1BB and CD28 in the immune response to influenza virus infection. Previous studies showed that CD28-/- mice have severely impaired primary and secondary CD8+ T cell expansion, which can be corrected by treatment with agonistic anti-4-1BB antibody. Although influenza-specific CD8+ T cells in ICOS-/- mice show only a small and transient defect late in the primary response, ICOS appears to be necessary for the anti-4-1BB-mediated recovery of immune responses in CD28-/-  mice. Furthermore, we show that ICOS and 4-1BB can cooperate to directly stimulate CD28-/- CD8+ T cells, which may have implications in human T cell responses in diseases characterized by accumulation of CD28- T cells. Although previous studies suggest a costimulatory role for 4-1BB, it was recently suggested that it also may have a negative regulatory role. Here we examine immune responses in 4-1BB-/- mice using two well-defined models and test several possible reasons for these conflicting results. We show that in the systemic influenza infection model 4-1BB plays a costimulatory role, but the adoptive transfer model using transgenic T cells shows that 4-1BB may be a negative regulator. The reasons for these apparently different roles of 4-1BB need to be further investigated.
Notes: Source: Dissertation Abstracts International, Volume: 68-01, Section: B, page: 0199.

Thesis (Ph.D.)--University of Toronto, 2006.

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