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Limited transplantation of antigen-expressing hematopoietic stem cells induces long-lasting cytotoxic T cell responses.

Denning WL, Xu J, Guo S, Klug CA, Hel Z - PLoS ONE (2011)

Bottom Line: Continuous antigen presentation by a limited number of differentiated transgenic hematopoietic cells results in an induction and prolonged maintenance of fully functional effector T cell responses in a mouse model.Majority of HSC-induced antigen-specific CD8+ T cells display central memory phenotype, efficiently kill target cells in vivo, and protect recipients against tumor growth in a preventive setting.Furthermore, we confirm previously published observation that high level engraftment of antigen-expressing HSCs following myeloablative conditioning results in tolerance and an absence of specific cytotoxic activity in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.

ABSTRACT
Harnessing the ability of cytotoxic T lymphocytes (CTLs) to recognize and eradicate tumor or pathogen-infected cells is a critical goal of modern immune-based therapies. Although multiple immunization strategies efficiently induce high levels of antigen-specific CTLs, the initial increase is typically followed by a rapid contraction phase resulting in a sharp decline in the frequency of functional CTLs. We describe a novel approach to immunotherapy based on a transplantation of low numbers of antigen-expressing hematopoietic stem cells (HSCs) following nonmyeloablative or partially myeloablative conditioning. Continuous antigen presentation by a limited number of differentiated transgenic hematopoietic cells results in an induction and prolonged maintenance of fully functional effector T cell responses in a mouse model. Recipient animals display high levels of antigen-specific CTLs four months following transplantation in contrast to dendritic cell-immunized animals in which the response typically declines at 4-6 weeks post-immunization. Majority of HSC-induced antigen-specific CD8+ T cells display central memory phenotype, efficiently kill target cells in vivo, and protect recipients against tumor growth in a preventive setting. Furthermore, we confirm previously published observation that high level engraftment of antigen-expressing HSCs following myeloablative conditioning results in tolerance and an absence of specific cytotoxic activity in vivo. In conclusion, the data presented here supports potential application of immunization by limited transplantation of antigen-expressing HSCs for the prevention and treatment of cancer and therapeutic immunization of chronic infectious diseases such as HIV-1/AIDS.

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Various hematopoietic lineages likely contribute to the induction of antigen-specific CD8+ T cells.Cell populations representing indicated hematopoietic lineages were isolated from the spleen and lymph nodes of OVA-transgenic mice by a combination of magnetic column purification and flow cytometry sorting as described in Methods. B6 mice were immunized i.v. by a single injection of 2×104 cells of the indicated lineage and the percentage of OVA-specific CD8+ T cells in blood was determined by pentamer staining at 2, 4, and 8 weeks post immunization. 3 animals per group; error bars represent standard errors.
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pone-0016897-g006: Various hematopoietic lineages likely contribute to the induction of antigen-specific CD8+ T cells.Cell populations representing indicated hematopoietic lineages were isolated from the spleen and lymph nodes of OVA-transgenic mice by a combination of magnetic column purification and flow cytometry sorting as described in Methods. B6 mice were immunized i.v. by a single injection of 2×104 cells of the indicated lineage and the percentage of OVA-specific CD8+ T cells in blood was determined by pentamer staining at 2, 4, and 8 weeks post immunization. 3 animals per group; error bars represent standard errors.

Mentions: Specific T cell responses in HSC-OVA recipients can be induced either directly by transgene-expressing professional antigen presenting cells or indirectly by antigen cross-presentation mechanism. To address the mechanism of specific T cell induction, naïve mice were immunized i.v. with 2×104 cells representing individual populations purified from OVA-transgenic mice. Immunization with DCs, B cells, NK cells, and cells of macrophage/monocyte lineage, but not T cells, induced detectable immune responses in recipients at 2 weeks post immunization (Fig. 6). However, in the absence of hematopoietic precursors, immune response subsided by 4 to 8 weeks post immunization.


Limited transplantation of antigen-expressing hematopoietic stem cells induces long-lasting cytotoxic T cell responses.

Denning WL, Xu J, Guo S, Klug CA, Hel Z - PLoS ONE (2011)

Various hematopoietic lineages likely contribute to the induction of antigen-specific CD8+ T cells.Cell populations representing indicated hematopoietic lineages were isolated from the spleen and lymph nodes of OVA-transgenic mice by a combination of magnetic column purification and flow cytometry sorting as described in Methods. B6 mice were immunized i.v. by a single injection of 2×104 cells of the indicated lineage and the percentage of OVA-specific CD8+ T cells in blood was determined by pentamer staining at 2, 4, and 8 weeks post immunization. 3 animals per group; error bars represent standard errors.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3040734&req=5

pone-0016897-g006: Various hematopoietic lineages likely contribute to the induction of antigen-specific CD8+ T cells.Cell populations representing indicated hematopoietic lineages were isolated from the spleen and lymph nodes of OVA-transgenic mice by a combination of magnetic column purification and flow cytometry sorting as described in Methods. B6 mice were immunized i.v. by a single injection of 2×104 cells of the indicated lineage and the percentage of OVA-specific CD8+ T cells in blood was determined by pentamer staining at 2, 4, and 8 weeks post immunization. 3 animals per group; error bars represent standard errors.
Mentions: Specific T cell responses in HSC-OVA recipients can be induced either directly by transgene-expressing professional antigen presenting cells or indirectly by antigen cross-presentation mechanism. To address the mechanism of specific T cell induction, naïve mice were immunized i.v. with 2×104 cells representing individual populations purified from OVA-transgenic mice. Immunization with DCs, B cells, NK cells, and cells of macrophage/monocyte lineage, but not T cells, induced detectable immune responses in recipients at 2 weeks post immunization (Fig. 6). However, in the absence of hematopoietic precursors, immune response subsided by 4 to 8 weeks post immunization.

Bottom Line: Continuous antigen presentation by a limited number of differentiated transgenic hematopoietic cells results in an induction and prolonged maintenance of fully functional effector T cell responses in a mouse model.Majority of HSC-induced antigen-specific CD8+ T cells display central memory phenotype, efficiently kill target cells in vivo, and protect recipients against tumor growth in a preventive setting.Furthermore, we confirm previously published observation that high level engraftment of antigen-expressing HSCs following myeloablative conditioning results in tolerance and an absence of specific cytotoxic activity in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.

ABSTRACT
Harnessing the ability of cytotoxic T lymphocytes (CTLs) to recognize and eradicate tumor or pathogen-infected cells is a critical goal of modern immune-based therapies. Although multiple immunization strategies efficiently induce high levels of antigen-specific CTLs, the initial increase is typically followed by a rapid contraction phase resulting in a sharp decline in the frequency of functional CTLs. We describe a novel approach to immunotherapy based on a transplantation of low numbers of antigen-expressing hematopoietic stem cells (HSCs) following nonmyeloablative or partially myeloablative conditioning. Continuous antigen presentation by a limited number of differentiated transgenic hematopoietic cells results in an induction and prolonged maintenance of fully functional effector T cell responses in a mouse model. Recipient animals display high levels of antigen-specific CTLs four months following transplantation in contrast to dendritic cell-immunized animals in which the response typically declines at 4-6 weeks post-immunization. Majority of HSC-induced antigen-specific CD8+ T cells display central memory phenotype, efficiently kill target cells in vivo, and protect recipients against tumor growth in a preventive setting. Furthermore, we confirm previously published observation that high level engraftment of antigen-expressing HSCs following myeloablative conditioning results in tolerance and an absence of specific cytotoxic activity in vivo. In conclusion, the data presented here supports potential application of immunization by limited transplantation of antigen-expressing HSCs for the prevention and treatment of cancer and therapeutic immunization of chronic infectious diseases such as HIV-1/AIDS.

Show MeSH
Related in: MedlinePlus