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. 2023 Oct 2;14:1231750. doi: 10.3389/fpsyt.2023.1231750

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Copyright © 2023 Klein, Guest, Dobrowolny and Steiner.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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Trafficking of myeloid cells and T-cells into brain parenchyma and hypothetical dependence retainment of T-cells on immune modulation by HSV. (A–D) Cascade of events illustrating what happens when brain parenchyma becomes involved in intracellular viral infection. The consecutive steps are: (A) release of chemokines and attraction of monocytes from the blood by interaction between neurons, glia and microglia; (B,C) strategic positioning of monocytes differentiated into DC/PVM in the BBB; and (D) eventual transmigration of T-cells into brain parenchyma dependent on HSV. In further detail, (A) primary response after parenchymal infection, production of CCL2, CXCL1, CXCL10 chemokines that attract monocytes from the blood compartment with binding to their counter-receptors (CCR2, CXCR1 and CXCL10, respectively) on the monocyte cell surface. (B) Positioning of the monocyte as differentiated DC/PVM into space between basal lamina (endothelial basement membrane) and glia limitans (parenchymal basement membrane). With positioning within the BBB, this cell expresses CD11c (CR4, complement receptor 4), CD163 and CD209. Again, chemokines released from brain parenchyma play a part in the positioning. (C) Retainment of T-cells in the BBB space. Without further parenchymal triggers and inflammatory processes going on in the brain parenchyma, these cells develop into Trm (responsive, high expressing grB) with a CD69+ CD103- phenotype (58). (D) Shows what may happen if HSV infects the DC/PVM and changes the milieu within the BBB. In this scenario, HSV-1 promotes production of tolerizing complement C4 and TGF-β, which may lead to transmigration of T-cells within the BBB into the brain parenchyma and differentiation into (unresponsive, low grB expressing) Trm-cells with a CD69+ CD103+ phenotype. This phenotype is preferentially retained in the parenchyma by binding to complementary receptors of glia and microglia. Trm-cells express PD1 and bind to PD-L1 on glia and Trm express CTLA4 that binds to CD86 on microglia. Figure created with biorender.com.