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Dissertation
The role of CD40 in dendritic cell induced CD8⁺ T cell responses
Doctor of Philosophy (Ph.D.), Drexel University
Jun 2003
DOI:
https://doi.org/10.17918/00007383
Abstract
CD8⁺ T cells are important for controlling intracellular pathogens and tumors through death of the target cell. Dendritic cells (DCs) are critical for the elicitation of CD8⁺ T cell responses. However, the factors that regulate DC immunostimulatory capacity are largely unknown. Here, we show that the elicitation of CD8⁺ T cell effector function is controlled by CD40 stimulation of DCs. By immunizing mice with bone marrow-derived DCs infected with live influenza virus, we show that the ligation of CD40 with CD40L trimer in vitro enhances effector differentiation of flu-specific CTLs in vivo. This does not occur with lipopolysaccharide, another classical activator of DC. Using CD40 -/- DCs, we also show that CD40 is required for the generation of these effector cells. Since this effect of CD40 could not be attributed to enhanced DC migration or upregulation of classical activation molecules, we performed gene expression microarray analysis, identifying 78 out of the 13,345 murine genes and ESTs that were uniquely and significantly regulated by CD40 stimulation, including known modulators of CD8⁺ T cell activation such as 4-1BBL, CD27L (CD70), IL-23 p19 subunit, and IL-15R [alpha] subunit. Finally, we tested whether the enhanced generation of effectors induced by CD40 stimulation of DCs during the primary response is accompanied by enhanced memory generation. We detected no differences in the CD8⁺ T cell memory response with respect to clonal expansion and effector generation between mice immunized with unstimulated, LPS-stimulated, and CD40-stimulated flu-infected DCs. However, wild-type mice immunized with CD40-/- flu-infected DCs had reduced absolute numbers of secondary flu-specific CTLs, and similarly, CD40-/- mice immunized with wild-type flu-infected DCs demonstrated deficiencies in CD8⁺ T cell recall responses to influenza. In conclusion, these data demonstrate that CD40 signaling on both the DC and presumably the CD8⁺ T cell is required for generating antiviral recall responses, while CD40 signaling on the DC is critical for mounting primary antiviral effector responses.
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Details
- Title
- The role of CD40 in dendritic cell induced CD8⁺ T cell responses
- Creators
- Alfred Hyoungju Kim
- Contributors
- Peter D. Katsikis (Advisor) - Drexel University, Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xiii, 211 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- College of Medicine; Drexel University
- Other Identifier
- 991021888740104721