Abstract
While the brain is considered an immune-privileged site, the CNS may nevertheless be the focus of immune mediated inflammation in the case of infection and certain autoimmune diseases, e.g., multiple sclerosis. As in other tissues, it has been found that acute T-cell infiltration may be followed by establishment of persistent local T-cell memory. To improve our understanding regarding the regulation of putative tissue resident memory T (Trm) cells in CNS, we devised a new model system for studying the generation of Trm cells in this site. To this purpose, we exploited the fact that the CNS may be a sanctuary for adenoviral infection, and to minimize virus-induced disease, we chose replication-deficient adenoviruses for infection of the CNS. Non-replicating adenoviruses are known to be highly immunogenic, and our studies demonstrate that intracerebral inoculation causes marked local T-cell recruitment, which is followed by persistent infiltration of the CNS parenchyma by antigen specific CD8+ T cells. Phenotypical analysis of CNS infiltrating antigen specific CD8+ T cells was consistent with these cells being Trms. Regarding the long-term stability of the infiltrate, resident CD8+ T cells expressed high levels of the anti-apoptotic molecule Bcl-2 as well as the proliferation marker Ki-67 suggesting that the population is maintained through steady homeostatic proliferation. Functionally, memory CD8+ T cells from CNS matched peripheral memory cells with regard to capacity for ex vivo cytotoxicity and cytokine production. Most importantly, our experiments revealed a key role for local antigen encounter in the establishment of sustained CD8+ T-cell memory in the brain. Inflammation in the absence of cognate antigen only led to limited and transient infiltration by antigen specific CD8+ T cells. Together these results indicate that memory CD8+ T cells residing in the CNS predominantly mirror previous local infections and immune responses to local autoantigens.
Highlights
It is well-known that T cells play a key role in the pathogenesis of many infections, autoimmunity and cancer
CD69 antagonizes the activity of the sphingosine 1-phospate receptor (S1P1), which is a critical regulator of T cell egress from most tissues [8], and CD103, which pairs with integrin β7 and mediates binding to E-cadherin, may be involved in the positioning and retention of the cells [9], CD103− Trms have been described in several tissues including the intestines, secondary lymphoid organs and liver [10,11,12,13,14]
To determine if it was possible to induce a lymphocyte infiltrate in the brain by inoculation of non-replicating adenovirus, WT mice (B6) were inoculated i.c. with 2 × 107 pfu of an adenovector expressing the GP of lymphocytic choriomeningitis virus (LCMV) tethered to the murine Ii chain for improved immunogenicity (AdIi-GP)
Summary
It is well-known that T cells play a key role in the pathogenesis of many infections, autoimmunity and cancer. In our experimental set-up the immunogenicity was in some cases even further improved by tethering of the antigen to the murine invariant (Ii) chain, which increases surface antigen presentation through mechanisms not fully understood [25, 26] Using these vectors we could mimic a non-lethal viral infection of the CNS; as antigen expression from adenovectors is known to be relatively long-standing, the induced response could serve as a model for an autoimmune response against the tissue/cells supporting persistence of the vector. Local antigen presentation is of critical importance in the recruitment of the effector cells, which develop into a persistent local memory population, and this was found to be the case whether we looked at adenovector induced responses or those following infection with live virus
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