Abstract
To better understand the initiation of CD8+ T cell responses during infection, the primary response to the intracellular parasite Toxoplasma gondii was characterized using 2-photon microscopy combined with an experimental system that allowed visualization of dendritic cells (DCs) and parasite specific CD8+ T cells. Infection with T. gondii induced localization of both these populations to the sub-capsular/interfollicular region of the draining lymph node and DCs were required for the expansion of the T cells. Consistent with current models, in the presence of cognate antigen, the average velocity of CD8+ T cells decreased. Unexpectedly, infection also resulted in modulation of the behavior of non-parasite specific T cells. This TCR-independent process correlated with the re-modeling of the lymph node micro-architecture and changes in expression of CCL21 and CCL3. Infection also resulted in sustained interactions between the DCs and CD8+ T cells that were visualized only in the presence of cognate antigen and were limited to an early phase in the response. Infected DCs were rare within the lymph node during this time frame; however, DCs presenting the cognate antigen were detected. Together, these data provide novel insights into the earliest interaction between DCs and CD8+ T cells and suggest that cross presentation by bystander DCs rather than infected DCs is an important route of antigen presentation during toxoplasmosis.
Highlights
Toxoplasma gondii is an intracellular protozoan parasite that induces a type 1 immune response characterized by the production of IFN-c from CD4+ and CD8+ T cells [1,2,3]
Dendritic cells are thought to play a vital role in the development of protective immunity to Toxoplasma gondii through their ability to produce immunological signals such as cytokines and process and present parasite derived peptides to T cells
Using the technology of live imaging by 2-photon microscopy we have identified a very early window of time during infection when dendritic cells and T cells make sustained contacts with one another, which appears crucial for the generation of protective responses
Summary
Toxoplasma gondii is an intracellular protozoan parasite that induces a type 1 immune response characterized by the production of IFN-c from CD4+ and CD8+ T cells [1,2,3] The generation of this protective T cell response is dependent on the early synthesis of IL-12 by innate immune cells such as DCs, macrophages and neutrophils [4,5]. Infection with T. gondii, results in an increase in the total numbers of DCs, their activation status (increase in levels of MHC I, MHC II, CD80 and CD86) and changes in subset composition [7] It is unclear from the earlier studies whether the depletion of DCs increases susceptibility to acute toxoplasmosis primarily through reduced IL-12 synthesis or by secondary effects on antigen presentation and T cell priming [6]. While there is considerable evidence that CD8+ T cells and DCs are required for the control of T. gondii [3,9], the actual interactions between these cells in vivo during toxoplasmosis have not been characterized
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