Naive and memory CD8+
T cells differ greatly with regards to their capacity to respond to antigenic stimulation. Activated/memory T cells secrete cytokines and proliferate immediately after antigen recognition. In contrast, naive CD8+
T cells undergo a series of phenotypic changes before differentiating into effector cells 12
. The mechanisms involved in the in vivo development of effector functions in naive CD8+
T cells still remain poorly understood. Indeed, the basic features of this T cell response, such as the time frame and sequence of events involved in the differentiation and proliferation of naive cells activated after infection by intracellular pathogens, have yet to be defined.
In rodent malaria models, it is well established that CD8+
T cells induced after immunization with attenuated or viable malaria sporozoites play an important role in protection against liver stages of this parasite. This has been demonstrated in adoptive transfer experiments using CD8+
T cell clones specific for defined malaria epitopes that inhibit parasite development in the liver, thus preventing the onset of blood-stage infection 34
. Moreover, immunization with subunit vaccines based on recombinant viruses or DNA-expressing MHC class I–restricted malaria epitopes induces a strong parasite-specific CD8+
T cell response that protects against parasite challenge 5678
. Overall, these studies demonstrate that in the malaria system, unlike most infectious models, CD8+
T cells exert such a strong antiparasitic effect that T cell responses against a single epitope can eliminate infection.
The induction of CD8+ T cells against the liver stages of malaria parasites differs from T cell responses to most infectious organisms. Soon after Plasmodium yoelii sporozoites invade hepatocytes, they undergo extensive transformation and about 44 h later, a distinct parasite stage, displaying a different antigenic make-up, is released from the liver and invade red blood cells. Since parasites from erythrocytic stages do not reinvade hepatocytes, the CD8+ T cell response against the liver stages is the result of a single and short-lived infectious event. In contrast, the CD8+ T cell responses to bacterial and viral infections are “shaped” by repeated overlapping cycles of infection and reinfection, generating a mixture of cell populations in different stages of differentiation.
A major limitation in analyzing the early in vivo events leading to the development of effector CD8+
T cells against malaria is the low frequency of precursors for specific epitopes. To overcome this limitation, we generated transgenic mice expressing a TCR specific for the H2Kd
-restricted epitope, SYVPSAEQI, located in the P. yoelii
circumsporozoite protein (amino acids 252–260). This epitope is recognized by CD8+
but not by CD4+
T cells 5
. Using this transgenic system, we sought to define the early events involved in the development of effector functions and acquisition of protective antiparasitic activity in naive malaria-specific CD8+