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

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.

• Authors: Heidi J Elsaesser, Mahmood Mohtashami, Ivan Osokine, Laura M Snell, Cameron R Cunningham, Giselle M Boukhaled, Dorian B McGavern, Juan Carlos Zúñiga-Pflücker, David G Brooks
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 117 Issue 10 Pg. 5420-5429 (03 10 2020) ISSN: 1091-6490 [Electronic] United States
• PMID: 32094187 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• B7-H1 Antigen
• Interferon Type I
• STAT2 Transcription Factor
• Stat2 protein, mouse

Topics

• Animals
• Atrophy (virology)
• B7-H1 Antigen (antagonists & inhibitors)
• CD8-Positive T-Lymphocytes (immunology, virology)
• Chronic Disease
• Hematopoietic Stem Cell Transplantation
• Interferon Type I (genetics, metabolism)
• Lymphocytic Choriomeningitis (immunology, pathology, therapy)
• Lymphocytic choriomeningitis virus
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• STAT2 Transcription Factor (metabolism)
• Signal Transduction
• Thymus Gland (pathology, virology)
• Virus Replication