Title

4-1BB costimulation in shaping T cell responses

Date of Completion

January 2005

Keywords

Health Sciences, Immunology

Degree

Ph.D.

Abstract

Immunization strategies have utilized agonist mAbies specific to the T cell costimulatory receptor 4-1BB to enhance and suppress specific immune responses. We combined 4-1BB with specific TLR adjuvants to study how these treatments would influence T cell expansion, contraction, memory and function. T cells primed in the presence of enforced 4-1BB costimulation had enhanced T cell accumulation that translated into profound acquisition of memory CD8 T cells able to proliferate and produce IFNγ upon recall, even up to 2 years post-immunization. We demonstrated that enforced 4-1BB can act directly on the T cell, regardless of 4-1BB expression on APCs, for an early accumulation and competitive advantage when compared to 4-1BB −/− T cells. Perhaps surprisingly, 4-1BB costimulation can also mediate immune suppression and we identified one mechanism of suppression mediated by CD8 T cells. Immunization with antigen, adjuvant, and agonist anti-4-1BB generated a population of antigen-specific CD8 T regulatory cells that inhibited CD4 T cells from cellular division. The mechanism of suppression required IFNγ, but IFNγ alone was not sufficient to suppress the CD4 T cells. Instead, the CD8 T cells had to engage IFNγ to suppress. We examined the suppression mechanism and showed that neutralizing TGFβ inhibited suppression. These data define a novel mechanism whereby IFNγ directly stimulates CD8 T regulatory cells to upregulate the bio-activity of TGFβ. This mechanism may help explain the conundrum of the dual role of 4-1BB, whereby immunity can be enhanced to mediate tumor clearance and suppressed to ameliorate autoimmunity. ^