Efficiently stimulated adult microglia cross‐prime naive CD8⁺T cells injected in the brain

Abstract

IntroductionThe brain parenchyma is a highly specialized immune site. The presence of the blood-brain barrier (BBB), lack of conventional lymphatic drainage, constitutive production of immunomodulatory cytokines and presence of microglia, profoundly control immune responses [1][2][3][4]. Microglia are now recognized as key players of the intrinsic brain immune system. Microglia develop either from (i) mesodermal precursors, that are thought to invade specific sites over the embryonic brain and to later colonize the brain parenchyma before formation of the BBB, or (ii) from blood or BM progenCorrespondence: Prof. Dominique Couez e-mail: dominique.couez@univ-angers.fr itors [5]. Resting microglia differ functionally and phenotypically from their peripheral counterparts and from CNS-associated macrophages and DCs [5][6][7], which are enclosed by a perivascular basement membrane within blood vessels. In the healthy adult brain, these resident innate immune cells are characterized by a highly ramified morphology, low CD45 and Fc receptor expression and low-to-undetectable expression of MHC class II (MHC-II) and costimulatory molecules [8][9][10]. These ramified microglia play a central role in the immune surveillance by monitoring environmental changes [11][12][13][14]. Through the expression of the patternrecognition receptors, including scavenger receptors and TLRs, microglia monitor both microbial and host-derived ligands within the CNS [15][16][17]. In response to injury, inflammation or neuronal degeneration, microglia are rapidly activated, migrate to the lesion site and proliferate. They secrete numerous cytokines, chemokines, neurotrophic and cytotoxic factors, gain phagocytic However, the in vivo cross-presentation capacity of resident microglia, within the brain microenvironment, remains undetermined. In response to injuries, peripheral and CNS-associated APCs infiltrate the brain parenchyma and are indistinguishable from activated microglia [5,9,[36][37][38], making it difficult to address the question of the cross-presentation capacity of resident microglia. We have thus set up an original protocol based on body irradiation, wherein the head is protected from irradiation. This protocol serves to remove functional peripheral and CNS-associated CD45 high APCs without affecting microglial function and resting status. In this aplasic mice model, we demonstrate for the first time that, despite the brain inhibitory constraints, resident microglia, under appropriate stimulation, cross-prime exogenous Ag to naive CD8 + T cells injected in the brain. Results Establishment of a model to analyze in vivo microglia cross presentationIn order to determine the capacity of microglia to cross-present exogenous Ag in situ, we set up a model excluding the involvement not only of peripheral APCs that infiltrate the brain in response to injuries but also of CNS-associated APCs, without affecting microglial function and activation status. Body irradiation eliminates peripheral APCsIn order to eliminate peripheral APCs, mice ha...

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