RRC ID 58428
Author Elsaesser HJ, Mohtashami M, Osokine I, Snell LM, Cunningham CR, Boukhaled GM, McGavern DB, Zúñiga-Pflücker JC, Brooks DG.
Title Chronic virus infection drives CD8 T cell-mediated thymic destruction and impaired negative selection.
Journal Proc Natl Acad Sci U S A
Abstract 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.
Volume 117(10)
Pages 5420-5429
Published 2020-3-10
DOI 10.1073/pnas.1913776117
PII 1913776117
PMID 32094187
PMC PMC7071912
MeSH Animals Atrophy / virology B7-H1 Antigen / antagonists & inhibitors CD8-Positive T-Lymphocytes / immunology* CD8-Positive T-Lymphocytes / virology* Chronic Disease Hematopoietic Stem Cell Transplantation Interferon Type I / genetics Interferon Type I / metabolism* Lymphocytic Choriomeningitis / immunology* Lymphocytic Choriomeningitis / pathology* Lymphocytic Choriomeningitis / therapy Lymphocytic choriomeningitis virus* Mice Mice, Inbred C57BL Mice, Transgenic STAT2 Transcription Factor / metabolism Signal Transduction Thymus Gland / pathology* Thymus Gland / virology* Virus Replication
IF 9.412
Times Cited 0
Mice RBRC01420