Antigen-specific clonal expansion and cytolytic effector function of CD8+ T lymphocytes depend on the transcription factor Bcl11b.
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.
Zhang
Shuning
S
Center for Cell Biology and Cancer Research, Albany Medical College, Albany, NY 12208, USA.
Rozell
Mike
M
Verma
Raj K
RK
Albu
Diana I
DI
Califano
Danielle
D
VanValkenburgh
Jeffrey
J
Merchant
Akeel
A
Rangel-Moreno
Javier
J
Randall
Troy D
TD
Jenkins
Nancy A
NA
Copeland
Neal G
NG
Liu
Pentao
P
Avram
Dorina
D
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
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