Fas ligand-mediated immune surveillance by T cells is essential for the control of spontaneous B cell lymphomas.
Loss of function of the tumor suppressor gene PRDM1 (also known as BLIMP1) or deregulated expression of the oncogene BCL6 occurs in a large proportion of diffuse large B cell lymphoma (DLBCL) cases. However, targeted mutation of either gene in mice leads to only slow and infrequent development of malignant lymphoma, and despite frequent mutation of BCL6 in activated B cells of healthy individuals, lymphoma development is rare. Here we show that T cells prevent the development of overt lymphoma in mice caused by Blimp1 deficiency or overexpression of Bcl6 in the B cell lineage. Impairment of T cell control results in rapid development of DLBCL-like disease, which can be eradicated by polyclonal CD8(+) T cells in a T cell receptor-, CD28- and Fas ligand-dependent manner. Thus, malignant transformation of mature B cells requires mutations that impair intrinsic differentiation processes and permit escape from T cell-mediated tumor surveillance.
1] Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. [2] Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia. [3].
Shoukat
S
Afshar-Sterle
1] Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. [2] Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia. [3].
Dimitra
D
Zotos
1] Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. [2] Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia. [3].
Nicholas J
NJ
Bernard
1] Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. [2] Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
Anna K
AK
Scherger
1] Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. [2] Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
Lisa
L
Rödling
1] Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. [2] Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
Amber E
AE
Alsop
1] Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. [2] Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
Jennifer
J
Walker
1] Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. [2] Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
Frederick
F
Masson
1] Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. [2] Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
Gabrielle T
GT
Belz
1] Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. [2] Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
Lynn M
LM
Corcoran
1] Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. [2] Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
Lorraine A
LA
O'Reilly
1] Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. [2] Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
Andreas
A
Strasser
1] Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. [2] School of Medicine, University of Queensland, Herston, Queensland, Australia.
Mark J
MJ
Smyth
1] Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. [2] Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.
Ricky
R
Johnstone
1] Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. [2] Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
David M
DM
Tarlinton
1] Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. [2] Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
Stephen L
SL
Nutt
1] Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. [2] Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
Axel
A
Kallies
D000818:Animals; D001402:B-Lymphocytes / Q000473:pathology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D002469:Cell Separation; D002471:Cell Transformation, Neoplastic; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D053222:Fas Ligand Protein / Q000378:metabolism*; D005434:Flow Cytometry; D016147:Genes, Tumor Suppressor; D007157:Immunologic Surveillance / Q000235:genetics; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D000074462:Positive Regulatory Domain I-Binding Factor 1; D051560:Proto-Oncogene Proteins c-bcl-6; D013601:T-Lymphocytes / Q000276:immunology*; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology
C490010:Bcl6 protein, mouse; D004268:DNA-Binding Proteins; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; C513258:Prdm1 protein, mouse; D051560:Proto-Oncogene Proteins c-bcl-6; D014157:Transcription Factors; D000074462:Positive Regulatory Domain I-Binding Factor 1