Abstract
To understand how the Bcl6 transcriptional repressor functions in the immune system, we disrupted its RD2 repression domain in mice. Bcl6RD2(MUT) mice exhibit a complete loss of germinal center (GC) formation but retain normal extrafollicular responses. Bcl6RD2(MUT) antigen-engaged B cells migrate to the interfollicular zone and interact with cognate T helper cells. However, these cells fail to complete early GC-commitment differentiation and coalesce as nascent GC aggregates. Bcl6 directly binds and represses trafficking receptors S1pr1 and Gpr183 by recruiting Hdac2 through the RD2 domain. Deregulation of these genes impairs B cell migration and may contribute to GC failure in Bcl6RD2(MUT) mice. The development of functional GC-TFH cells was partially impaired in Bcl6RD2(MUT) mice. In contrast to Bcl6(-/-) mice, Bcl6RD2(MUT) animals experience no inflammatory disease or macrophage deregulation. These results reveal an essential role for RD2 repression in early GC commitment and striking biochemical specificity in Bcl6 control of humoral and innate immune-cell phenotypes.
Highlights
In response to T-cell dependent (TD) antigen stimulation, antigen-specific B-cells migrate to the periphery of B-cell follicles and interfollicular zones of secondary lymphoid organs, where they interact with cognate T-helper cells within 1-3 days (Kerfoot et al, 2011; Okada et al, 2005; Qi et al, 2008)
We found that RD2 domain is essential for pre-germinal center (GC) B-cell differentiation and clustering into nascent GC within follicles, in part through repressing key trafficking receptors S1pr1 and Gpr183 by recruiting Hdac2
It was reported that the bcl6 middle region containing the RD2 domain binds to histone deacetylase 2 (HDAC2), MTA3/NuRD complex and CtBP (Bereshchenko et al, 2002; Fujita et al, 2004; Mendez et al, 2008)
Summary
In response to T-cell dependent (TD) antigen stimulation, antigen-specific B-cells migrate to the periphery of B-cell follicles and interfollicular zones of secondary lymphoid organs, where they interact with cognate T-helper cells within 1-3 days (Kerfoot et al, 2011; Okada et al, 2005; Qi et al, 2008). B-cells can follow one of three alternative fates by differentiating into extrafollicular plasma cells, follicular germinal center (GC) B-cells or recirculating early memory B-cells (McHeyzer-Williams et al, 2012). T follicular helper (TFH) cells express the chemokine receptor CXCR5 and costimulatory molecule PD-1 at high levels and specialize in providing help to B-cells during the humoral immune response (Crotty, 2011). Interactions with cognate B-cells, especially GC B-cells within GCs, are critical for further polarization, maintenance and function of TFH-cells at later stages of the immune response (Choi et al, 2011; Kerfoot et al, 2011; Kitano et al, 2011). The reciprocal development of GC Bcells and TFH-cells is crucial for establishment of the GC reaction, including formation of high-affinity antibody and generation of long-live plasma cells
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.