The Fates of Dendritic Cells and Antigen Regulate CD4+ T Cell Responses
The rapid activation of effector T cells by antigen-presenting dendritic cells (DCs) is necessary to contain and eradicate pathogens. Upon eradication of the pathogens by effector T cells, the immune response eventually resolves, and the clearance of residual antigen is necessary to prevent immune cell exhaustion or immunopathology. It has been proposed that the elimination of antigen-presenting DCs by CD8+ cytotoxic T cells (CTLs) limits the duration of antigen presentation, hence resolving ongoing immune responses. However, inter-DC antigen transfer spreads antigens for further antigen presentation and may reduce the effect of CTL-mediated DC killing. The aim of my thesis was to examine the impact of CTL-mediated DC killing and inter-DC antigen transfer on the induction and the quality of resulting T cell responses. Initial experiments established that CTLs eliminated antigen-bearing DCs mainly through the cytolytic molecule perforin, whereas FasL played a minor role. CTL-mediated DC killing prevented antigen-bearing DCs from stimulating naive CD4+ and CD8+ T cells in the draining lymph nodes. Thus, CTLs regulated the clonal expansion of naive T cells by controlling the survival of antigen-presenting DCs. The efficiency of CTL-mediated DC killing depended on the method of antigen loading onto DCs, and to a lesser extent, the method of generating CTLs. Surprisingly, efficient CTL-mediated DC killing that completely prevented the accumulation of injected DCs in the lymph nodes did not abolish T cell proliferation, indicating that other antigen presenting cells (APCs) were inducing the residual T cell proliferation when the antigen-bearing DCs were eliminated by CTLs. Further investigations revealed that the antigen from the injected DCs was transferred to host DCs. In the absence of direct antigen presentation by injected DCs, host DCs stimulated local T cell proliferation but did not induce a systemic effector T cell response. In contrast, in the presence of efficient CTL-mediated DC killing, inter-DC antigen transfer enabled the host DCs to stimulate T cell proliferation. These T cells then developed into iii functional effector T cells. In conclusion, in the absence of inter-DC antigen transfer, CTLmediated DC killing reduces the size of T cell responses. However, in the presence of inter- DC antigen transfer, the impact of CTL-mediated DC killing is reduced, hence influencing the size and quality of T cell responses. My findings shed light on how CTL-mediated DC killing and inter-DC antigen transfer regulate immune responses and how DC vaccine regimens for immunotherapy can be improved.