RGD Reference Report - Chronic virus infection drives CD8 T cell-mediated thymic destruction and impaired negative selection. - Rat Genome Database

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Chronic virus infection drives CD8 T cell-mediated thymic destruction and impaired negative selection.

Authors: Elsaesser, Heidi J  Mohtashami, Mahmood  Osokine, Ivan  Snell, Laura M  Cunningham, Cameron R  Boukhaled, Giselle M  McGavern, Dorian B  Zúñiga-Pflücker, Juan Carlos  Brooks, David G 
Citation: Elsaesser HJ, etal., Proc Natl Acad Sci U S A. 2020 Mar 10;117(10):5420-5429. doi: 10.1073/pnas.1913776117. Epub 2020 Feb 24.
RGD ID: 42722006
Pubmed: (View Article at PubMed) PMID:32094187
DOI: Full-text: DOI:10.1073/pnas.1913776117

Chronic infection provokes alterations in inflammatory and suppressive pathways that potentially affect the function and integrity of multiple tissues, impacting both ongoing immune control and restorative immune therapies. Here we demonstrate that chronic lymphocytic choriomeningitis virus infection rapidly triggers severe thymic depletion, mediated by CD8 T cell-intrinsic type I interferon (IFN) and signal transducer and activator of transcription 2 (Stat2) signaling. Occurring temporal to T cell exhaustion, thymic cellularity reconstituted despite ongoing viral replication, with a rapid secondary thymic depletion following immune restoration by anti-programmed death-ligand 1 (PDL1) blockade. Therapeutic hematopoietic stem cell transplant (HSCT) during chronic infection generated new antiviral CD8 T cells, despite sustained virus replication in the thymus, indicating an impairment in negative selection. Consequently, low amounts of high-affinity self-reactive T cells also escaped the thymus following HSCT during chronic infection. Thus, by altering the stringency and partially impairing negative selection, the host generates new virus-specific T cells to replenish the fight against the chronic infection, but also has the potentially dangerous effect of enabling the escape of self-reactive T cells.

Annotation

Disease Annotations    

Objects Annotated

Genes (Rattus norvegicus)
Stat2  (signal transducer and activator of transcription 2)

Genes (Mus musculus)
Stat2  (signal transducer and activator of transcription 2)

Genes (Homo sapiens)
STAT2  (signal transducer and activator of transcription 2)


Additional Information