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Unique transcriptional profile of liver-resident memory CD8+ T cells induced by immunization with malaria sporozoites.

Tse SW, Cockburn IA, Zhang H, Scott AL, Zavala F - Genes Immun. (2013)

Bottom Line: Sterile immunity against live Plasmodium infection can be achieved by immunization with radiation-attenuated sporozoites.This protection is known to be mediated in part by antigen-specific memory CD8(+) T cells, presumably those residing in the liver.We found major differences in the expression of immune function genes as well as genes involved in the cell cycle, cell trafficking, transcription and intracellular signaling.

View Article: PubMed Central - PubMed

Affiliation: W. Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.

ABSTRACT
Sterile immunity against live Plasmodium infection can be achieved by immunization with radiation-attenuated sporozoites. This protection is known to be mediated in part by antigen-specific memory CD8(+) T cells, presumably those residing in the liver. We characterized and compared the transcriptional profile of parasite-specific memory CD8(+) T cells residing in the liver and spleen after immunization of mice with irradiated sporozoites. Microarray-based expression analysis of these memory CD8(+) T cells indicated that liver-resident memory cells display a distinct gene expression profile. We found major differences in the expression of immune function genes as well as genes involved in the cell cycle, cell trafficking, transcription and intracellular signaling. Importantly, the malaria parasite-induced liver-resident CD8(+) T cells display a transcriptional profile different to that described for CD8(+) T cells following other microbial challenges.

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GSEA analysis of liver-resident memory CD8Py T cellsProtein expression of (A) GZMB and (B) CD69 among spleen and liver memory CD8Py. (C-E) GSEA was performed to determine whether up-regulated effector genes set [19] (C), repeated immunization gene set [21] (D) and exhaustion associated gene set [22] (E) show specific enrichment to liver memory CD8Py induced by irradiated sporozoite immunization. (F) Fold changes (as liver/spleen) of selected exhaustion markers in sorted Thy1.1+CD8+ memory cells from mice immunized with irradiated P. yoelii sporozoites. Dotted lines represent fold-change cutoff = 1.8, * indicates FDR < 0.1 (G) Histograms showing expression of CTLA-4, LAG3, CD160 and PD1. Plots are gated on Thy1.1+ CD8Py. Data are representative of three experiments.
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Figure 6: GSEA analysis of liver-resident memory CD8Py T cellsProtein expression of (A) GZMB and (B) CD69 among spleen and liver memory CD8Py. (C-E) GSEA was performed to determine whether up-regulated effector genes set [19] (C), repeated immunization gene set [21] (D) and exhaustion associated gene set [22] (E) show specific enrichment to liver memory CD8Py induced by irradiated sporozoite immunization. (F) Fold changes (as liver/spleen) of selected exhaustion markers in sorted Thy1.1+CD8+ memory cells from mice immunized with irradiated P. yoelii sporozoites. Dotted lines represent fold-change cutoff = 1.8, * indicates FDR < 0.1 (G) Histograms showing expression of CTLA-4, LAG3, CD160 and PD1. Plots are gated on Thy1.1+ CD8Py. Data are representative of three experiments.

Mentions: The higher levels of production of the effector protein GZMB (Fig. 6A) and CD69 (Fig. 6B), a marker of recent TCR engagement, suggested that the transcriptional profile of memory resident liver CD8+ T cells may correspond to an ‘effector’ phenotype. To explore this possibility, we compared the gene signature of liver-PyCD8 memory cells to the expression profile previously described for effector CD8+ T cells induced by LCMV infection [19]. GSEA [18] revealed that parasite-induced liver-PyCD8 memory cells did not resemble the profile described for effector cells induced by LCMV as they do not have a significant enrichment of genes that were uniquely up-regulated in the anti-LCMV effector CD8+ T cells (Fig. 6C).


Unique transcriptional profile of liver-resident memory CD8+ T cells induced by immunization with malaria sporozoites.

Tse SW, Cockburn IA, Zhang H, Scott AL, Zavala F - Genes Immun. (2013)

GSEA analysis of liver-resident memory CD8Py T cellsProtein expression of (A) GZMB and (B) CD69 among spleen and liver memory CD8Py. (C-E) GSEA was performed to determine whether up-regulated effector genes set [19] (C), repeated immunization gene set [21] (D) and exhaustion associated gene set [22] (E) show specific enrichment to liver memory CD8Py induced by irradiated sporozoite immunization. (F) Fold changes (as liver/spleen) of selected exhaustion markers in sorted Thy1.1+CD8+ memory cells from mice immunized with irradiated P. yoelii sporozoites. Dotted lines represent fold-change cutoff = 1.8, * indicates FDR < 0.1 (G) Histograms showing expression of CTLA-4, LAG3, CD160 and PD1. Plots are gated on Thy1.1+ CD8Py. Data are representative of three experiments.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3722257&req=5

Figure 6: GSEA analysis of liver-resident memory CD8Py T cellsProtein expression of (A) GZMB and (B) CD69 among spleen and liver memory CD8Py. (C-E) GSEA was performed to determine whether up-regulated effector genes set [19] (C), repeated immunization gene set [21] (D) and exhaustion associated gene set [22] (E) show specific enrichment to liver memory CD8Py induced by irradiated sporozoite immunization. (F) Fold changes (as liver/spleen) of selected exhaustion markers in sorted Thy1.1+CD8+ memory cells from mice immunized with irradiated P. yoelii sporozoites. Dotted lines represent fold-change cutoff = 1.8, * indicates FDR < 0.1 (G) Histograms showing expression of CTLA-4, LAG3, CD160 and PD1. Plots are gated on Thy1.1+ CD8Py. Data are representative of three experiments.
Mentions: The higher levels of production of the effector protein GZMB (Fig. 6A) and CD69 (Fig. 6B), a marker of recent TCR engagement, suggested that the transcriptional profile of memory resident liver CD8+ T cells may correspond to an ‘effector’ phenotype. To explore this possibility, we compared the gene signature of liver-PyCD8 memory cells to the expression profile previously described for effector CD8+ T cells induced by LCMV infection [19]. GSEA [18] revealed that parasite-induced liver-PyCD8 memory cells did not resemble the profile described for effector cells induced by LCMV as they do not have a significant enrichment of genes that were uniquely up-regulated in the anti-LCMV effector CD8+ T cells (Fig. 6C).

Bottom Line: Sterile immunity against live Plasmodium infection can be achieved by immunization with radiation-attenuated sporozoites.This protection is known to be mediated in part by antigen-specific memory CD8(+) T cells, presumably those residing in the liver.We found major differences in the expression of immune function genes as well as genes involved in the cell cycle, cell trafficking, transcription and intracellular signaling.

View Article: PubMed Central - PubMed

Affiliation: W. Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.

ABSTRACT
Sterile immunity against live Plasmodium infection can be achieved by immunization with radiation-attenuated sporozoites. This protection is known to be mediated in part by antigen-specific memory CD8(+) T cells, presumably those residing in the liver. We characterized and compared the transcriptional profile of parasite-specific memory CD8(+) T cells residing in the liver and spleen after immunization of mice with irradiated sporozoites. Microarray-based expression analysis of these memory CD8(+) T cells indicated that liver-resident memory cells display a distinct gene expression profile. We found major differences in the expression of immune function genes as well as genes involved in the cell cycle, cell trafficking, transcription and intracellular signaling. Importantly, the malaria parasite-induced liver-resident CD8(+) T cells display a transcriptional profile different to that described for CD8(+) T cells following other microbial challenges.

Show MeSH
Related in: MedlinePlus