title: Antigen-specific clonal expansion and cytolytic effector function of CD8+ T lymphocytes depend on the transcription factor Bcl11b.
abstract: CD8(+) T lymphocytes mediate the immune response to viruses, intracellular bacteria, protozoan parasites, and tumors. We provide evidence that the transcription factor Bcl11b/Ctip2 controls hallmark features of CD8(+) T cell immunity, specifically antigen (Ag)-dependent clonal expansion and cytolytic activity. The reduced clonal expansion in the absence of Bcl11b was caused by altered proliferation during the expansion phase, with survival remaining unaffected. Two genes with critical roles in TCR signaling were deregulated in Bcl11b-deficient CD8(+) T cells, CD8 coreceptor and Plcgamma1, both of which may contribute to the impaired responsiveness. Bcl11b was found to bind the E8I, E8IV, and E8V, but not E8II or E8III, enhancers. Thus, Bcl11b is one of the transcription factors implicated in the maintenance of optimal CD8 coreceptor expression in peripheral CD8(+) T cells through association with specific enhancers. Short-lived Klrg1(hi)CD127(lo) effector CD8(+) T cells were formed during the course of infection in the absence of Bcl11b, albeit in smaller numbers, and their Ag-specific cytolytic activity on a per-cell basis was altered, which was associated with reduced granzyme B and perforin.
authors.affiliation: Center for Cell Biology and Cancer Research, Albany Medical College, Albany, NY 12208, USA.
authors.forename: Shuning
authors.initials: S
authors.lastname: Zhang
authors.forename: Mike
authors.initials: M
authors.lastname: Rozell
authors.forename: Raj K
authors.initials: RK
authors.lastname: Verma
authors.forename: Diana I
authors.initials: DI
authors.lastname: Albu
authors.forename: Danielle
authors.initials: D
authors.lastname: Califano
authors.forename: Jeffrey
authors.initials: J
authors.lastname: VanValkenburgh
authors.forename: Akeel
authors.initials: A
authors.lastname: Merchant
authors.forename: Javier
authors.initials: J
authors.lastname: Rangel-Moreno
authors.forename: Troy D
authors.initials: TD
authors.lastname: Randall
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Jenkins
authors.forename: Neal G
authors.initials: NG
authors.lastname: Copeland
authors.forename: Pentao
authors.initials: P
authors.lastname: Liu
authors.forename: Dorina
authors.initials: D
authors.lastname: Avram
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D017209:Apoptosis / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D016827:CD8 Antigens / Q000235:genetics / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D049109:Cell Proliferation; D002999:Clone Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D004742:Enhancer Elements, Genetic / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation / Q000502:physiology; D053804:Granzymes / Q000235:genetics / Q000378:metabolism; D008089:Listeria monocytogenes / Q000235:genetics / Q000276:immunology; D008088:Listeriosis / Q000276:immunology / Q000382:microbiology; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009976:Orthomyxoviridae Infections / Q000276:immunology; D010047:Ovalbumin / Q000235:genetics / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D051966:Phospholipase C gamma / Q000235:genetics; D052899:Pore Forming Cytotoxic Proteins / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000378:metabolism
chemical_list: C511143:Bcl11b protein, mouse; D016827:CD8 Antigens; C431698:CD8alpha antigen; C477867:CD8beta antigen; C110366:OVA-8; D010446:Peptide Fragments; D052899:Pore Forming Cytotoxic Proteins; D011948:Receptors, Antigen, T-Cell; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; C483886:perforin, mouse; D010047:Ovalbumin; D051746:ZAP-70 Protein-Tyrosine Kinase; C497262:Zap70 protein, mouse; D051966:Phospholipase C gamma; D053804:Granzymes