Differential Regulation of Effector- and Central-Memory Responses to Toxoplasma gondii Infection by IL-12 Revealed by Tracking of Tgd057-Specific CD8+ T Cells
Production of the pro-inflammatory cytokine IL-12 by innate phagocytes drives the differentiation of IFN-γ-producing effector T cells during Toxoplasma gondii infection. However, the role of IL-12 in the regulation of memory CD8+ T cell differentiation and function during murine toxoplasmosis is unc...
| Main Authors: | , , , , , , , |
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| Format: | Article |
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Public Library of Science (PLoS)
2018
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| Online Access: | http://hdl.handle.net/1721.1/116198 https://orcid.org/0000-0002-1090-6071 |
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| author | Wilson, Douglas C. Grotenbreg, Gijsbert M. Liu, Kenian Zhao, Yanlin Frickel, Eva-Maria Gubbels, Marc-Jan Yap, George S. Ploegh, Hidde |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Wilson, Douglas C. Grotenbreg, Gijsbert M. Liu, Kenian Zhao, Yanlin Frickel, Eva-Maria Gubbels, Marc-Jan Yap, George S. Ploegh, Hidde |
| author_sort | Wilson, Douglas C. |
| collection | MIT |
| description | Production of the pro-inflammatory cytokine IL-12 by innate phagocytes drives the differentiation of IFN-γ-producing effector T cells during Toxoplasma gondii infection. However, the role of IL-12 in the regulation of memory CD8+ T cell differentiation and function during murine toxoplasmosis is unclear. To track memory CTL development, we identified a novel H-2Kb-restricted CTL population specific for the Toxoplasma antigen tgd057. Tgd057-specific CTLs were induced by both vaccination and natural peroral infection, and were representative of the polyclonal CTL population. Tgd057-specific primary effector cells required IL-12 for the differentiation of KLRG1+ effector subpopulations and IFN-γ production in response to restimulation with parasite-infected cells, but not to restimulation with cognate peptide. The effect of IL-12 deficiency during the primary response was profoundly imprinted on memory CTLs, which continued to show defects in cell numbers, KLRG1+ effector memory subpopulation differentiation, and IFN-γ recall responses. Importantly, isolated CD62Lhi KLRG1- CD8+ T cells differentiated in the absence of IL-12 were enhanced in their ability to generate IFN-γ-producing secondary tgd057-specific effector cells. Our data, for the first time, demonstrate the negative impact of IL-12 signaling on the quality of the central memory CTL compartment. Thus, despite the beneficial role of IL-12 in promoting effector differentiation, excessive exposure to IL-12 during CTL priming may limit the development of long-term protective immunity through the decreased fitness of central memory CTL responses. |
| first_indexed | 2024-09-23T09:36:39Z |
| format | Article |
| id | mit-1721.1/116198 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T09:36:39Z |
| publishDate | 2018 |
| publisher | Public Library of Science (PLoS) |
| record_format | dspace |
| spelling | mit-1721.1/1161982022-09-26T12:38:30Z Differential Regulation of Effector- and Central-Memory Responses to Toxoplasma gondii Infection by IL-12 Revealed by Tracking of Tgd057-Specific CD8+ T Cells Wilson, Douglas C. Grotenbreg, Gijsbert M. Liu, Kenian Zhao, Yanlin Frickel, Eva-Maria Gubbels, Marc-Jan Yap, George S. Ploegh, Hidde Massachusetts Institute of Technology. Department of Biology Ploegh, Hidde Production of the pro-inflammatory cytokine IL-12 by innate phagocytes drives the differentiation of IFN-γ-producing effector T cells during Toxoplasma gondii infection. However, the role of IL-12 in the regulation of memory CD8+ T cell differentiation and function during murine toxoplasmosis is unclear. To track memory CTL development, we identified a novel H-2Kb-restricted CTL population specific for the Toxoplasma antigen tgd057. Tgd057-specific CTLs were induced by both vaccination and natural peroral infection, and were representative of the polyclonal CTL population. Tgd057-specific primary effector cells required IL-12 for the differentiation of KLRG1+ effector subpopulations and IFN-γ production in response to restimulation with parasite-infected cells, but not to restimulation with cognate peptide. The effect of IL-12 deficiency during the primary response was profoundly imprinted on memory CTLs, which continued to show defects in cell numbers, KLRG1+ effector memory subpopulation differentiation, and IFN-γ recall responses. Importantly, isolated CD62Lhi KLRG1- CD8+ T cells differentiated in the absence of IL-12 were enhanced in their ability to generate IFN-γ-producing secondary tgd057-specific effector cells. Our data, for the first time, demonstrate the negative impact of IL-12 signaling on the quality of the central memory CTL compartment. Thus, despite the beneficial role of IL-12 in promoting effector differentiation, excessive exposure to IL-12 during CTL priming may limit the development of long-term protective immunity through the decreased fitness of central memory CTL responses. 2018-06-11T14:52:23Z 2018-06-11T14:52:23Z 2010-03 2009-04 2018-06-08T18:40:20Z Article http://purl.org/eprint/type/JournalArticle 1553-7374 1553-7366 http://hdl.handle.net/1721.1/116198 Wilson, Douglas C. et al. “Differential Regulation of Effector- and Central-Memory Responses to Toxoplasma Gondii Infection by IL-12 Revealed by Tracking of Tgd057-Specific CD8+ T Cells.” Edited by Eric Y. Denkers. PLoS Pathogens 6, 3 (March 2010): e1000815 © 2010 Wilson et al https://orcid.org/0000-0002-1090-6071 http://dx.doi.org/10.1371/journal.ppat.1000815 PLoS Pathogens Attribution 4.0 International (CC BY 4.0) https://creativecommons.org/licenses/by/4.0/ application/pdf Public Library of Science (PLoS) PLoS |
| spellingShingle | Wilson, Douglas C. Grotenbreg, Gijsbert M. Liu, Kenian Zhao, Yanlin Frickel, Eva-Maria Gubbels, Marc-Jan Yap, George S. Ploegh, Hidde Differential Regulation of Effector- and Central-Memory Responses to Toxoplasma gondii Infection by IL-12 Revealed by Tracking of Tgd057-Specific CD8+ T Cells |
| title | Differential Regulation of Effector- and Central-Memory Responses to Toxoplasma gondii Infection by IL-12 Revealed by Tracking of Tgd057-Specific CD8+ T Cells |
| title_full | Differential Regulation of Effector- and Central-Memory Responses to Toxoplasma gondii Infection by IL-12 Revealed by Tracking of Tgd057-Specific CD8+ T Cells |
| title_fullStr | Differential Regulation of Effector- and Central-Memory Responses to Toxoplasma gondii Infection by IL-12 Revealed by Tracking of Tgd057-Specific CD8+ T Cells |
| title_full_unstemmed | Differential Regulation of Effector- and Central-Memory Responses to Toxoplasma gondii Infection by IL-12 Revealed by Tracking of Tgd057-Specific CD8+ T Cells |
| title_short | Differential Regulation of Effector- and Central-Memory Responses to Toxoplasma gondii Infection by IL-12 Revealed by Tracking of Tgd057-Specific CD8+ T Cells |
| title_sort | differential regulation of effector and central memory responses to toxoplasma gondii infection by il 12 revealed by tracking of tgd057 specific cd8 t cells |
| url | http://hdl.handle.net/1721.1/116198 https://orcid.org/0000-0002-1090-6071 |
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