CD103+ CD8 T Cells in the Toxoplasma-Infected Brain Exhibit a Tissue-Resident Memory Transcriptional Profile

Abstract

During chronic infection, memory T cells acquire a unique phenotype and become dependent on different survival signals than those needed for memory T cells generated during an acute infection. The distinction between the role of effector and memory T cells in an environment of persistent antigen remains unclear. Here, in the context of chronic Toxoplasma gondii infection, we demonstrate that a population of CD8 T cells exhibiting a tissue-resident memory (TRM) phenotype accumulates within the brain. We show that this population is distributed throughout the brain in both parenchymal and extraparenchymal spaces. Furthermore, this population is transcriptionally distinct and exhibits a transcriptional signature consistent with the TRM observed in acute viral infections. Finally, we establish that the CD103+ TRM population has an intrinsic capacity to produce both IFN-γ and TNF-α, cytokines critical for parasite control within the central nervous system (CNS). The contribution of this population to pro-inflammatory cytokine production suggests an important role for TRM in protective and ongoing immune responses in the infected CNS.Accession number: GSE95105

Tissue‐resident memory T cells in tissue homeostasis, persistent infection, and cancer surveillance

“…Like innate lymphocytes, resting T RM cells contain elevated levels of transcripts encoding a number of pro‐inflammatory cytokines, meaning that they are poised for rapid cytokine production upon appropriate stimulation . In line with this, CD8 + CD69 + CD103 + T RM cells isolated from various mouse and human tissues exhibit enhanced production of cytokines, such as IFNɣ, TNFα, IL‐2, and IL‐17, as well as target cell killing, upon re‐stimulation ex vivo . Rapid cytokine production by T RM cells has also been confirmed in vivo .…”

“…Despite this heterogeneity, many T RM types display overlapping transcriptional features that distinguish them from their counterparts in the circulation . For instance, murine CD8 + T RM cells from skin, lung, gut and brain share a core transcriptional signature consisting of uniformly up‐ or down‐regulated genes associated with cell adhesion (eg, Itgae , Itga1 , Cdh1 ), migration (eg, S1pr1, S1pr5 , Rgs1 , Rgs2, Xcl1 , Cxcr6 ), immune regulation (eg, Cd244 , Ctla4 , Pdcd1 , Icos , Tlr1 ) and transcriptional activity (eg, Klf2 , Hobit , Eomes , Nr4a1, Nr4a2 , Litaf , Ahr ), as well as genes encoding enzymes with largely unknown functions in T cells (eg, Hpgds , Inpp4b , Qpct , Cmah ) . Many of these genes are similarly regulated in CD8 + T RM cells from human tissues, meaning that certain features of T RM transcriptional profiles are conserved between mice and humans.…”

Brains and Brawn: Toxoplasma Infections of the Central Nervous System and Skeletal Muscle

“…Live multi-photon imaging visualized a number of different T cell behaviors in the brain including division, random search strategies and sustained interactions with CNS resident and peripheral antigen presenting cells [22, 49, 50, 56]. Flow cytometry and histological studies further show that in an infected brain CD4+ and CD8+ T cells can express markers of tissue residency [64], exhaustion (e.g. PD-1) [22, 65–67] or are PD-1 negative and secrete IFN-γ.…”

TCR-MHC Interaction Strength Defines Trafficking and Resident Memory Status of CD8 T cells in the Brain

“…Persistent antigen stimulation has been shown to lower CD103 expression on T RM but it did not block their formation (54). It is possible that these cells become exhausted when constantly stimulated and thus only newly formed CD103 positive cells contribute to the cells observed in the brain (23). It is possible that the strength of the antigen stimulation influences this process and lower affinity leads to lower number of R7-III cells expressing CD103, eventually leading to the elimination of these cells.…”