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Eva Frickel group project:

Properties and phenotype of memory CD8 T cells in the Toxoplasma gondii-infected brain

Through their production of IFNγ, CD8 T cells are important in conferring resistance against Toxoplasma. After an infection with Toxoplasma, both CD4 and CD8 T cells infiltrate the brain. Thus far only transgenic parasites expressing model antigens in combination with transgenic T cells have been used as models for infection. Obvious shortcomings of this approach include difficulties in controlling expression levels and localization of the antigen, and moreover the model transgenic T cell receptors might not recognise the model antigen with physiological affinity.

We have identified H-2L^d-restricted CD8 T cell epitopes derived from two distinct Toxoplasma proteins, dense granule protein GRA4 and rhoptry protein ROP7. GRA4-specific T cells are detected during acute infection, whereas T cells reactive to the ROP7 peptide persist during the chronic phase. T cells secrete protective IFNγ during both phases of infection.

We have also identified a H-2K^b restricted CD8 T cell epitope from the uncharacterized parasite protein Tgd057. Another H-2L^d-restricted CD8 epitope from GRA6 has been described. Using flow cytometry to sort antigen-specific CD8 T cells from Toxoplasma-infected BL/6 x Balb/c F1 mice, transnuclear (TN) Toxoplasma-specific CD8 T cell receptor (TCR) mice for all four of these Toxoplasma epitope-MHC complexes (L^d-Rop7, L^d-Gra4, L^d-Gra6 and K^b-tgd057) have been generated by somatic cell nuclear transfer. We have three lines of mice with unique TCR sequences that all recognize L^d-Rop7, thus enabling further studies on how the binding affinity of the TCR to the MHC controls parasite burden.

Using these tools we will investigate the cellular localization of the Toxoplasma antigens and their molecular processing requirements. We will explore whether the antigen-specific CD8 T cells are protective during the acute phase of a Toxoplasma infection.

TN T cell function in vivo

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(A) Optical imaging of luciferase-expressing Toxoplasma during a lethal challenge and quantification of signal (B) Data plotted are results, mean ± SEM. *** indicates significant difference (2-way ANOVA, p-value < 0.001)