CD8⁺ T cell priming and provision of CD4⁺ T cell help are spatially and temporally distinct events

Abstract

The generation of a protective memory CD8⁺ T cell response requires priming of naïve T cells by dendritic cells and consecutive proliferation and differentiation of CD8⁺ T cells. In this differentiation process CD8⁺ T cells integrate multiple signals, including TCR-mediated stimulation, co-stimulation as well as cytokine-mediated activation. Co-stimulation and cytokine-mediated activation are in part dependent on CD4⁺ T cell helper signals. However, CD4⁺ T cell help for CD8⁺ T cells is not directly transmitted but rather provided by an intermediate cell population - dendritic cells.<br /> In this study, I investigated which DC subset serves as the critical communication platform between CD4⁺ T helper and CD8⁺ T cells in order to optimize CD8⁺ T cell priming. Additionally, I aimed to address the spatio-temporal dynamics of such interactions in vivo, asking when and where those interactions may take place during an antiviral immune response. Interestingly, I found that CD4⁺ and CD8⁺ T cells were initially primed on spatial separated DC. CD8⁺ T cells were activated on directly infected DC in the periphery of the LN whereas CD4⁺ T cells were activated on non-infected DC in the LN paracortex. Notably, only during the later phase of infection (> 24h), both CD4⁺ and CD8⁺ T cells interacted with antigen-presenting non-infected XCR1⁺ DC within the paracortex of the LN. This critical activation step happened after the initial DC encounter of both lymphocyte subsets, but before they started to proliferate. On a functional level, I found that anti-viral CD8⁺ T cell responses activated in the absence of XCR1⁺ DC failed to differentiate into fully functional memory CD8⁺ T cells, mimicking the lack of CD4⁺ T cell help.<br /> In conclusion, this study identifies a new phase of T cell programing that reveals multiple DC interactions during the initial lymphocyte priming step, is critical for the development of a functional memory CD8⁺ T cell compartment.