Abstract
T cell exhaustion is common during chronic infections and can prevent optimal immunity. Although recent studies have demonstrated the importance of inhibitory receptors and other pathways in T cell exhaustion, the underlying transcriptional mechanisms are unknown. Here, we define a role for the transcription factor Blimp-1 in CD8(+) T cell exhaustion during chronic viral infection. Blimp-1 repressed key aspects of normal memory CD8(+) T cell differentiation and promoted high expression of inhibitory receptors during chronic infection. These cardinal features of CD8(+) T cell exhaustion were corrected by conditionally deleting Blimp-1. Although high expression of Blimp-1 fostered aspects of CD8(+) T cell exhaustion, haploinsufficiency indicated that moderate Blimp-1 expression sustained some effector function during chronic viral infection. Thus, we identify Blimp-1 as a transcriptional regulator of CD8(+) T cell exhaustion during chronic viral infection and propose that Blimp-1 acts as a transcriptional rheostat balancing effector function and T cell exhaustion.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Acute Disease
-
Animals
-
Antigens, CD / immunology
-
Antigens, CD / metabolism
-
Antigens, Surface / immunology
-
Antigens, Surface / metabolism
-
Apoptosis Regulatory Proteins / immunology
-
Apoptosis Regulatory Proteins / metabolism
-
CD8-Positive T-Lymphocytes / immunology*
-
CD8-Positive T-Lymphocytes / metabolism
-
CD8-Positive T-Lymphocytes / virology
-
Cell Differentiation / immunology
-
Chronic Disease
-
Cytotoxicity, Immunologic / immunology
-
GPI-Linked Proteins
-
Granzymes / immunology
-
Granzymes / metabolism
-
Immunologic Memory / immunology*
-
Lymphocyte Activation Gene 3 Protein
-
Lymphocytic Choriomeningitis / immunology
-
Lymphocytic Choriomeningitis / virology
-
Lymphocytic choriomeningitis virus / immunology
-
Mice
-
Mice, Inbred C57BL
-
Mice, Knockout
-
Mice, Transgenic
-
Positive Regulatory Domain I-Binding Factor 1
-
Programmed Cell Death 1 Receptor
-
Receptors, Immunologic / immunology
-
Receptors, Immunologic / metabolism
-
Signaling Lymphocytic Activation Molecule Family
-
Transcription Factors / genetics
-
Transcription Factors / metabolism*
-
Virus Diseases / genetics
-
Virus Diseases / immunology*
Substances
-
Antigens, CD
-
Antigens, Surface
-
Apoptosis Regulatory Proteins
-
Cd160 protein, mouse
-
Cd244a protein, mouse
-
GPI-Linked Proteins
-
Pdcd1 protein, mouse
-
Prdm1 protein, mouse
-
Programmed Cell Death 1 Receptor
-
Receptors, Immunologic
-
Signaling Lymphocytic Activation Molecule Family
-
Transcription Factors
-
Positive Regulatory Domain I-Binding Factor 1
-
Granzymes
-
Lymphocyte Activation Gene 3 Protein