Differential Regulation of Effector- and Central-Memory Responses to Toxoplasma gondii Infection by IL-12 Revealed by Tracking of Tgd057-Specific CD8+ T Cells

PLoS Pathogens

Douglas C. Wilson¹  George S. Yap¹  Yanlin Zhao¹  Kenian Liu¹  Marc-Jan Gubbels²  Gijsbert M. Grotenbreg³  Hidde L. Ploegh⁴  Eva-Maria Frickel⁴ 

[1] Center for Immunity and Inflammation, UMDNJ-New Jersey Medical School, Newark, New Jersey, United States of America;Department of Biology, Boston College, Chestnut Hill, Massachusetts, United States of America;Immunology Programme and Departments of Microbiology and Biological Sciences, National University of Singapore, Singapore;Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, United States of America

关键词: T cells;    Cytotoxic T cells;    Toxoplasma gondii;    Cell differentiation;    Parasitic diseases;    Spleen;    Memory T cells;    Memory;   

DOI  :  10.1371/journal.ppat.1000815

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY