Selective Upregulation of Transcripts for Six Molecules Related to T Cell Costimulation and Phagocyte Recruitment and Activation among 734 Immunity-Related Genes in the Brain during Perforin-Dependent, CD8⁺T Cell-Mediated Elimination of Toxoplasma gondii Cysts

Abstract

We recently found that an invasion of CD8+ cytotoxic T cells into tissue cysts of Toxoplasma gondii initiates an elimination of the cysts in association with an accumulation of microglia and macrophages. In the present study, we compared mRNA levels for 734 immune-related genes in the brains of infected SCID mice that received perforin-sufficient or -deficient CD8+ immune T cells at 3 weeks after infection. At 7 days after the T cell transfer, mRNA levels for only six genes were identified to be greater in the recipients of the perforin-sufficient T cells than in the recipients of the perforin-deficient T cells. These six molecules included two T cell costimulatory molecules, inducible T cell costimulator receptor (ICOS) and its ligand (ICOSL); two chemokine receptors, C-X-C motif chemokine receptor 3 (CXCR3) and CXCR6; and two molecules related to an activation of microglia and macrophages, interleukin 18 receptor 1 (IL-18R1) and chitinase-like 3 (Chil3). Consistently, a marked reduction of cyst numbers and upregulation of ICOS, CXCR3, CXCR6, IL-18R1, and Chil3 mRNA levels were also detected when the perforin-sufficient CD8+ immune T cells were transferred to infected SCID mice at 6 weeks after infection, indicating that the CD8+ T cell-mediated protective immunity is capable of eliminating mature T. gondii cysts. These results together suggest that ICOS-ICOSL interactions are crucial for activating CD8+ cytotoxic immune T cells to initiate the destruction of T. gondii cysts and that CXCR3, CXCR6, and IL-18R are involved in recruitment and activation of microglia and macrophages to the T cell-attacked cysts for their elimination. IMPORTANCE T. gondii establishes a chronic infection by forming tissue cysts, which can grow into sizes greater than 50 μm in diameter as a consequence of containing hundreds to thousands of organisms surrounded by the cyst wall within infected cells. Our recent studies using murine models uncovered that CD8+ cytotoxic T cells penetrate into the cysts in a perforin-dependent manner and induce their elimination, which is accompanied with an accumulation of phagocytic cells to the T cell-attacked target. This is the first evidence of the ability of the T cells to invade into a large target for its elimination. However, the mechanisms involved in anticyst immunity remain unclear. Immune profiling analyses of 734 immune-related genes in the present study provided a valuable foundation to initiate elucidating detailed molecular mechanisms of the novel effector function of the immune system operated by perforin-mediated invasion of CD8+ T cells into large targets for their elimination.

The role of IL-1 family of cytokines and receptors in pathogenesis of COVID-19

“…IL‐18 facilitates IFN-γ production by CD4 + T cells, NK cells, B cells, DCs, and MQs with the help of IL‐12, since IL-12 significantly increases the expression of IL‐18R [ 105 , 106 ]. Moreover, IL‐18, with synergistic effects of IL-12 and IL-15, up-regulates perforin and Fas ligand (FasL) expression and promotes FasL‐dependent cytotoxicity in NK cells and CD8 + T cells [ 107 , 108 ]. Additionally, studies suggested that IL-18, in synergy with IL-23, enhances IL-17 production by Th-17 cells [ 104 ].…”

IFN-γ production by brain-resident cells activates cerebral mRNA expression of a wide spectrum of molecules critical for both innate and T cell-mediated protective immunity to control reactivation of chronic infection with Toxoplasma gondii

“…Microglia activated by IFN-γ are able to kill tachyzoites in vitro ( Chao et al., 1993 ). Whereas the direct evidence on an expression of CXCR3 on microglia in the brain during T. gondii infection is not available yet, our recent studies demonstrated that CXCR3 expression significantly increases during CD8 + T cell-mediated anti- T. gondii cyst immune responses ( Lutshumba et al., 2020 ), in which Iba1 + microglia and Ly6C + inflammatory macrophages accumulate to the cysts and phagocytose bradyzoites within the cysts for their elimination ( Tiwari et al., 2019 ). Therefore, it is possible that CXCR3 + microglia accumulate into the areas of tachyzoite proliferation and phagocytose them to kill the parasite.…”

CircRNA and miRNA expression analysis in livers of mice with Toxoplasma gondii infection

“…Previous omics studies have provided a wealth of resources that improved understanding of the pathogenesis of T. gondii ( Garfoot et al., 2019 ; Antil et al., 2021 ; Menard et al., 2021 ; Antil et al., 2022 ), and many studies mainly focused on mRNAs ( He et al., 2016 ; Zhou et al., 2016 ; Lutshumba et al., 2020 ). Recently, Zhou and colleagues revealed putative functions of miRNAs and circRNAs in brains of mice after an infection with T. gondii ( Zhou et al., 2020 ).…”