Feedback Interactions between Dendritic Cells and CD8+ T Cells during the Development of Type-1 Immunity
CD8+ T cell responses are crucial for immunity against intracellular infections and can mediate tumor regression. While CD8+ T cells are widely recognized as cytolytic effector cells (cytolytic T cells; CTLs), little is known about their immunoregulatory functions and their impact on dendritic cells (DCs). A similar area of controversy is the role of DC in regulating the induction of CD8+ T cell effector functions and CD8+ T cell memory. This dissertation addresses the impact of bidirectional communication between DCs and CD8+ T cells, during different phases of the immune response, upon the functions of both these cell types.
In order to reconcile the apparently contrasting notions that CD8+ T cells perform both suppressor and helper functions, I compared the DC-modulating activity of CD8+ T cells at different stages of activation. I observed that DC-killing and DC-activating (and protective) functions are exerted sequentially by activated CD8+ T cells. In contrast to the effector cells that kill DCs in a granzyme B/perforin-dependent manner, memory CD8+ T cells promote IL-12 production in DCs and support CD4+ and CD8+ T cell responses. Moreover, memory CD8+ T cells instruct DC to over-express granzyme B inhibitor PI-9, protecting them from elimination by CTLs. I observed that the inclusion of heterologous CD8+ T cell epitopes in cancer vaccines, promoting the interaction of vaccine-bearing DCs with large numbers of tumor-unrelated CD8+ T cells, strongly enhances the immunologic and therapeutic activity of vaccination against established tumors that are resistant to standard vaccines.
Since the character of the vaccination-induced CD8+ T cells is important for the efficacy of cancer immunotherapy, I have analyzed the role of DCs in influencing the cytolytic function and peripheral tissue-homing ability of CD8+ T cells. I observed that short-term-activated inflammatory-type DCs, capable of producing high levels of IL-12 and other pro-inflammatory cytokines, support induction of cytotoxic function and a switch from lymphoid to peripheral chemokine receptors in CD8+ T cells. In contrast, exhausted DCs matured for extended periods of time or matured under the influence of the mediators of chronic inflammation, favor CD8+ T cell expansion alone without acquisition of effector functions.
Collectively, the findings presented in this dissertation broaden our understanding of the feedback circuitry between CD8+ T cells and DCs and will help us to design improved vaccines against cancer and chronic infections.
Advisor:Lisa H. Butterfield; Albert D. Donnenberg; Todd Reinhart; Charles R. Rinaldo; Walter J. Storkus; Pawel Kalinski
School:University of Pittsburgh
School Location:USA - Pennsylvania
Source Type:Master's Thesis
Date of Publication:11/16/2007