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CCR7-Dependent T Cell-Mediated Immunity During Toxoplasma gondii Infection


Infection with the protozoan parasite, Toxoplasma gondii is one of the most prevalent human infections and has been targeted by CDC (Centers for Disease Control and Prevention) as a priority for public health action. Its been recognized as a ``silent killer'' because of its ability to cause a latent infection in the host brain without any significant symptoms, unless the host is immunocompromised. Thus, it is an important concern to the ever-increasing AIDS (acquired immune deficiency syndrome) community or people on immunosuppressive therapies. In addition, immune responses following Toxoplasma infection in an immunocompetent host represent finely tuned host immunity that grants the parasite survival but robust enough to provide protection against the parasite and thus, avoiding serious illness. A thorough understanding of the key components of this balanced protective immunity may help to design efficient strategies to maximize immune responses for the host benefit.

Chemokines are a family of small molecules secreted by host cells and can induce diverse biological responses in nearby responsive cells. They are important immunomodulatory agents coordinating leukocyte migration during homeostasis and inflammation. This dissertation highlights a lymphoid chemokine receptor CCR7 (C-C chemokine receptor 7) as an essential component of the host protective immunity during both the acute and the chronic phase of Toxoplasma infection although through separate mechanisms. Host protective immunity during Toxoplasma infection is mainly T cell-mediated. This dissertation demonstrates that CCR7 is an absolute requirement for the generation of protective immunity during the acute phase of infection. CCR7-deficient mice succumb in the early phase of infection due to a delay in T cell priming. Further investigation reveals that the requirement of CCR7 to optimize T cell priming is eventually compensated during the chronic phase of infection, however, CCR7 is required for T cell migration within the infected CNS that influences their ability to control the parasite burden at this stage. Although there is no defect in the antigen-specificity or the influx of effector T cells in the infected brain, CCR7-deficient mice are unable to mount protective memory responses following secondary infection. This dissertation provides new insights about the hallmarks for protective immunity in such a balanced chronic infection scenario as well as reveals new mechanisms as to how this lymphoid chemokine signaling influences important immunological processes in the peripheral tissues particularly in the CNS.

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