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

Abstract

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.

The Toxoplasma gondii Peptide AS15 Elicits CD4 T Cells That Can Control Parasite Burden

“…Secretion of parasite antigens into the host cell is known to be important for presentation via the MHC class I pathway, which samples the host cytosol and stimulates CD8 T cell responses to intracellular pathogens. This is in line with evidence that secretion into the host cell promotes recognition by CD8 T cells (31) and the fact that all of the T. gondii CD8 epitopes identified to date are derived from secreted parasite proteins (4,16,40,62). On the other hand, the impact of secretion on MHC class II presentation of potential parasite antigens is less clear, since both secreted and nonsecreted parasite antigens should have ready access to the class II MHC pathway via phagocytosis of intact parasites and debris.…”

“…This approach has been used to examine CD8 T cell responses to T. gondii, leading to the identification of a number of endogenous CD8 antigens (4,7,16,40,62). Most strikingly, mice possessing the MHC-I molecule L d mount an immunodominant response to the HF10 decapeptide derived from the T. gondii protein GRA6 (4).…”

Marginal Zone B Cells Regulate Antigen-Specific T Cell Responses during Infection

“…Hence parasitespecific CD8 T cells are primed in a low-Ag, IL-12-poor environment. This could explain why only a small percentage of effector CD8 T cells expresses KLRG1 and 70-80% of the CD8 surviving contraction are T CM -like cells (31).…”

“…2B). A recent study demonstrated that the generation of KLRG1 + effector CD8 T cells is governed by IL-12 (31). Thus, we assessed the IL-12 p35 and IL-12/IL-23 p40 mRNA expression by splenic CD11c hi DCs at days 1, 3, and 6 after L. donovani infection.…”

Importância da resposta aos epítopos subdominantes, da proliferação e da recirculação de linfócitos T CD8+ durante a vacinação experimental contra a infecção pelo Trypanosoma cruzi.

“…Finally, our observations may have important implications regarding the basis for the strong immunodominance pattern observed after experimental infection with other intracellular parasites such as Plasmodium, Toxoplasma gondii and Theileria parva [50,51,[54][55][56][57].…”