Direct presentation regulates the magnitude of the CD8+ T cell response to cell-associated antigen through prolonged T cell proliferation (130.32)

Abstract The magnitude and complexity of antigen-specific CD8+ T cell responses is determined by both intrinsic properties of the immune system and extrinsic factors such as vaccination. We evaluated mechanisms that regulate the CD8+ T cell response to two distinct determinants derived from the same protein antigen, SV40 T antigen (T Ag), in C57BL/6 mice following immunization with T Ag transformed cells. We found that the immunodominance hierarchy was reversed in a dose-dependent manner by addition of excess naïve T cells targeting the subdominant epitope. However, competition by T cells targeting distinct determinants played only a minor role in limiting T cell accumulation under physiological conditions. In contrast, the magnitude of the T cell response was regulated by the ability of T Ag transformed cells to directly present the T Ag determinants. The hierarchy of the CD8+ T cell response was maintained when antigen presentation in vivo was restricted to cross-presentation, but immunization with T Ag transformed cells capable of direct presentation dramatically enhanced T cell accumulation at the peak of the response. Enhanced accumulation was due to a prolonged period of T cell proliferation, resulting in a delay in T cell contraction. Our findings reveal that direct presentation by non-professional antigen presenting cells can dramatically enhance accumulation of CD8+ T cells during the primary response, revealing a potential strategy to enhance vaccination approaches.