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Dissection of effector vs memory phases of CTL responses inc. studies in K/O mice

preclinical study dataset

Data were produced in our lab on a broad spectrum of priming events and their impact on the effector and memory phases of the CTL response.

Activation of a cytotoxic T lymphocyte (CTL) response in an antigen-exposed lymph node involves a great diversity of encounters between naive CTLs and APCs that differ in both duration and quality. This broad spectrum of priming events instigates a complex blend of CTL developmental pathways.

Using an experimental system that allows tight control over CTL priming, we have singled out defined priming events and analyzed the impact of the resulting instructional program on the effector and memory phases of the CTL response. As expected, prolonged antigenic stimulation induces potent CTL expansion, effector function and CTL memory. In contrast, CTL that have received suboptimal stimulation fail to undergo extensive expansion. Nevertheless these arrested CTL persist long term and acquire memory function in the absence of further cell division. Thus our data demonstrate that CTL memory can develop as a result of a suboptimal stimulation that causes arrested clonal expansion.

The effect of environmental factors on development of high affinity CTL was investigated using a system whereby OT-1 cells were primed in vitro by engineered APC. After a 20 h priming phase, CTL were transferred to recipient mice that were either naïve, or had been injected with activated dendritic cells one day earlier, thus creating a reactive lymph node. Note that the reactive lymph node that is thus created does not harbour specific antigen. Using this system we are able to separate cognate antigenic and co-stimulatory signals that were uniformly delivered by the APC in vitro, from environmental factors such as growth factors, which are present in the reactive lymph node. Although primary responses were not affected by a reactive lymph node environment, responses to secondary antigenic challenge of CTL that had developed in a reactive lymph node were significantly enhanced. Experiments using CD40 and IL-12 knock out mice and IL-7R blocking antibody suggest that these factors do not play a role. IL-15 is a likely candidate molecule mediating the observed effect, but in the (genetic) absence of IL-15 memory cells do not survive and no secondary responses could be detected.






created over 9 years ago (2 March 2009)    last modified over 6 years ago (28 September 2011)   [ RDF Rdf ]   [ RelFinder Relfinder ]