CD40 signaling drives B lymphocytes into an intermediate memory-like state, poised between naïve and plasma cells.
Immunological memory comprising of antigen-specific B and T cells contributes to the acquisition of long-term resistance to pathogens. Interactions between CD40 on B cells and CD40L on T cells are responsible for several aspects of acquired immune responses including generation of memory B cells. In order to gain insights into events leading to memory B cell formation, we analyzed the genome-wide expression profile of murine naive B cells stimulated in the presence of anti-CD40. We have identified over 8,000 genes whose expression is altered minimally 1.5-fold at least at one time point over a 3-day time course. The array analysis indicates that changes in expression level of maximum number of these genes occur within 24 h of anti-CD40 treatment. In parallel, we have studied the events following CD40 ligation by examining the expression of known regulators of naive B cell to plasma cell transition, including Pax5 and BLIMP1. The expression profile of these regulatory genes indicates firstly, that CD40 signaling activates naïve B cells to a phenotype that is intermediate between the naive and plasma cell stages of the B cell differentiation. Secondly, the major known regulator of plasma cell differentiation, BLIMP1, gets irreversibly downregulated upon anti-CD40 treatment. Additionally, our data reveal that CD40 signaling mediated BLIMP1 downregulation occurs by non-Pax5/non-Bcl6 dependent mechanisms, indicating novel mechanisms at work that add to the complexity of understanding of B cell master regulatory molecules like BLIMP1 and Pax5.
Centre for Cellular and Molecular Biology, Hyderabad, 500007, India.
Mala
M
Upadhyay
G Krishna
GK
Priya
P
P
Ramesh
M B
MB
Madhavi
Satyajit
S
Rath
Vineeta
V
Bal
Anna
A
George
Tushar
T
Vaidya
D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D019013:CD40 Antigens / Q000378:metabolism*; D002454:Cell Differentiation; D002478:Cells, Cultured; D042002:Chromatin Assembly and Disassembly; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D020868:Gene Silencing; D005838:Genotype; D007156:Immunologic Memory / Q000187:drug effects / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D020411:Oligonucleotide Array Sequence Analysis; D051757:PAX5 Transcription Factor / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D010950:Plasma Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D000074462:Positive Regulatory Domain I-Binding Factor 1; D051560:Proto-Oncogene Proteins c-bcl-6; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
C490010:Bcl6 protein, mouse; D019013:CD40 Antigens; D004268:DNA-Binding Proteins; D008070:Lipopolysaccharides; D051757:PAX5 Transcription Factor; C497282:Pax5 protein, mouse; C513258:Prdm1 protein, mouse; D051560:Proto-Oncogene Proteins c-bcl-6; D014157:Transcription Factors; D000074462:Positive Regulatory Domain I-Binding Factor 1