Pronounced virus-dependent activation drives exhaustion but sustains IFN-γ transcript levels.
During many chronic infections, the responding CD8 T cells become exhausted as they progressively lose their ability to elaborate key effector functions. Unlike prototypic memory CD8 cells, which rapidly synthesize IFN-gamma following activation, severely exhausted T cells fail to produce this effector molecule. Nevertheless, the ontogeny of exhausted CD8 T cells, as well as the underlying mechanisms that account for their functional inactivation, remains ill defined. We have used cytokine reporter mice, which mark the transcription of IFN-gamma mRNA by the expression of Thy1.1, to decipher how activation events during the early stages of a chronic infection dictate the development of exhaustion. We show that virus-specific CD8 T cells clearly respond during the early stages of chronic lymphocytic choriomeningitis virus infection, and that this early T cell response is more pronounced than that initially observed in acutely infected hosts. Thus, exhausted CD8 T cells appear to emerge from populations of potently activated precursors. Unlike acute infections, which result in massive expansion of the responding T cells, there is a rapid attenuation of further expansion during chronic infections. The exhausted T cells that subsequently emerge in chronically infected hosts are incapable of producing the IFN-gamma protein. Surprisingly, high levels of the IFN-gamma transcript are still present in exhausted cells, demonstrating that ablation of IFN-gamma production by exhausted cells is not due to transcriptional silencing. Thus, posttranscription regulatory mechanisms likely disable this effector module.
Mackerness
Kathryn J
KJ
Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Cox
Maureen A
MA
Lilly
Lauren M
LM
Weaver
Casey T
CT
Harrington
Laurie E
LE
Zajac
Allan J
AJ
D000208:Acute Disease; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology / Q000821:virology*; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D002908:Chronic Disease; D055879:Gene Knock-In Techniques; D020868:Gene Silencing / Q000276:immunology*; D017930:Genes, Reporter / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D008216:Lymphocytic Choriomeningitis / Q000276:immunology / Q000473:pathology / Q000821:virology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D013234:Stem Cells / Q000276:immunology / Q000473:pathology / Q000821:virology; D018800:Thy-1 Antigens / Q000096:biosynthesis / Q000235:genetics; D014158:Transcription, Genetic / Q000276:immunology*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D014775:Virus Activation / Q000276:immunology
D018800:Thy-1 Antigens; D007371:Interferon-gamma