Indiana University-Purdue University Indianapolis (IUPUI) / The transcriptional repressor BCL6 has been shown to be essential for the differentiation
of germinal center (GC) B cells and follicular T helper (TFH) cells. The interaction of
TFH and GC B cells is necessary for the development of high affinity antibodies specific
for an invading pathogen. Germline BCL6-deficient mouse models limit our ability to
study BCL6 function in T cells due to the strong inflammatory responses seen in these
mice. To overcome this, our lab has developed a new BCL6 conditional knockout (cKO)
mouse using the cre/lox system, wherein the zinc finger region of the BCL6 gene is
flanked by loxP sites. Mating to a CD4-Cre mouse allowed us to study the effects of
BCL6 loss specifically in T cells, without the confounding effects seen in germline
knockout models. Using this cKO model, we have reaffirmed the necessity of BCL6 for
TFH differentiation, including its role in sustained CXCR5 surface expression, a
signature marker for TFH cells. This model also allowed us to recognize the role of
BCL6 in promoting the expression of PD-1, another key surface marker for TFH cells.
Without BCL6, CD4+ T cells cannot express PD-1 at the high levels seen on TFH cells.
Our discovery of DNMT3b as a target for BCL6 suggests BCL6-deficient T cells have
increased DNA methyltransferase activity at the PD-1 promoter. This data establishes a
novel pathway for explaining how BCL6, a transcriptional repressor, can activate genes.
Experiments with the BCL6 cKO model have also established a role for BCL6 in naïve
CD4+ T cell activation. Furthermore, we did not observe increased differentiation of
other helper T cell subsets, in contrast to what has been reported elsewhere with
germline BCL6-deficient models. Unexpectedly, we found decreased T helper type 2
(Th2) cells, whereas mouse models with a germline mutation of BCL6 have increased
Th2 cells. These results indicate that BCL6 activity in non-T cells is critical for controlling
T cell differentiation. Finally, using an HIV-1 gp120 immunization model, we have, for
the first time, shown BCL6-dependent GCs to be limiting for antibody development and
affinity maturation in a prime-boost vaccine scheme.
| Identifer | oai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/5930 |
| Date | January 2014 |
| Creators | Hollister, Kristin N. |
| Contributors | Dent, Alexander L., Brutkiewicz, Randy R., Harrington, Maureen A., Kaplan, Mark H. |
| Source Sets | Indiana University-Purdue University Indianapolis |
| Language | en_US |
| Detected Language | English |
| Type | Thesis |
| Rights | Attribution-NonCommercial-NoDerivs 3.0 United States, http://creativecommons.org/licenses/by-nc-nd/3.0/us/ |
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