REGULATION OF ADAPTIVE IMMUNE RESPONSES TO PLASMODIUM CHABAUDI MALARIA INFECTION
Malaria killed an estimated of 437,000 people last year, most of them children. While there is a vaccine nearly licensed, it only induces limited and short-lived protection. A major problem in the development of an effective vaccine is the poor understanding of the mechanisms that generate protective immunity. In malaria, IFN-γ+ CD4 T cell responses, called T helper type 1 (Th1), are necessary to control acute parasite growth. On the other hand, IL-21+ T follicular helper (Tfh) cells are essential for generating high-affinity antibodies for parasite clearance. Whereas the transcription factors Bcl6, Blimp-1, and STAT3 regulate the development of Tfh cells, T-bet and STAT4 direct the commitment of Th1 cells. Since our understanding of the regulation of adaptive protective responses against malaria is poor, the present dissertation aimed to study the development of CD4 T cell responses using the murine parasite Plasmodium chabaudi, which models chronic human malaria immunology and pathology. First, we show that the CD4 T cell response against malaria consists mostly of a newly described Th1-like Tfh hybrid population. We demonstrated that these cells express both T-bet and Bcl6 in the nucleus and survive into the memory pool. Second, we used Bcl6, Blimp-1 and STAT3 T cell-specific conditional knock out (TKO) mice to study their roles in the generation of the Th1-like Tfh subset. We found that the Bcl6/Blimp-1 axis regulates the expression of the Tfh chemokine receptor CXCR5, but only Blimp-1 deficiency increased the proportions of Th1-like Tfh cells. STAT3 TKO mice had more IFN-γ+ Th1 memory cells, and were protected from reinfection. Since persistent immune stimulation can promote Tfh development, we treated mice at day 3 post infection with the antimalarial mefloquine (MQ) to reduce immune stimulation early in our system. This early MQ treatment resulted in a great expansion of IFN-γ+ Th1 cells and a great reduction of Th1-like Tfh cells. In conclusion, our studies have provided vital information describing the adaptive immune responses during chronic malaria infection. Moreover, our data has identified several molecules for future studies to help the rational development of a much-needed vaccine.
Networked Digital Library of Theses and Dissertations
The University of Texas Medical Branch at Galveston