Germinal center entry not selection of B cells is controlled by peptide-MHCII complex density.
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2018-03-02
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B cells expressing high affinity antigen receptors are advantaged in germinal centers (GC), perhaps by increased acquisition of antigen for presentation to follicular helper T cells and improved T-cell help. In this model for affinity-dependent selection, the density of peptide/MHCII (pMHCII) complexes on GC B cells is the primary determinant of selection. Here we show in chimeric mice populated by B cells differing only in their capacity to express MHCII (MHCII+/+ and MHCII+/-) that GC selection is insensitive to halving pMHCII density. Alone, both B cell types generate identical humoral responses; in competition, MHCII+/+ B cells are preferentially recruited to early GCs but this advantage does not persist once GCs are established. During GC responses, competing MHCII+/+ and MHCII+/- GC B cells comparably accumulate mutations and have indistinguishable rates of affinity maturation. We conclude that B-cell selection by pMHCII density is stringent in the establishment of GCs, but relaxed during GC responses.
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Yeh, Chen-Hao, Takuya Nojima, Masayuki Kuraoka and Garnett Kelsoe (2018). Germinal center entry not selection of B cells is controlled by peptide-MHCII complex density. Nature communications, 9(1). p. 928. 10.1038/s41467-018-03382-x Retrieved from https://hdl.handle.net/10161/19410.
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Chen-Hao Yeh
Dr. Yeh completed his undergraduate and Master of Science degree at the National Taiwan University in Taipei. He then pursued his Ph.D. at the University of Tokyo in Japan. He moved to Durham in 2015 for postdoctoral training in Dr. Garnett Kelsoe’s laboratory at the Duke Department of Immunology.
Dr. Yeh holds a broad academic background in biochemistry and immunology, with specific training and expertise in lymphocyte development and differentiation. His research has focused on: 1) germinal center (GC) B cell selection, differentiation and antibody affinity maturation and 2) T follicular helper (Tfh) cell differentiation and TCR repertoire analysis.
Over the years, Dr. Yeh has demonstrated that B-cell selection based on surface pMHCII density is stringent in the establishment of GCs, but relatively relaxed during GC responses; this observation has led to fundamental revisions in the standard models for affinity-driven selection. With multiple genetic models to identify GC-resident Tfh cells in the mouse, Dr. Yeh also showed that the standard phenotypic definition of “GCTfh” included a majority of T cells that do not enter GCs. The more abundant Tfh-like cells have distinct developmental requirements, TCR repertoires and transcriptomic profiles compared to the rarer GC-resident Tfh cells, implying distinct physiologies and function. In addition, Dr. Yeh has categorized the phenotype of memory and GC B cell populations in Rhesus macaque (RM) as a step forward in understanding humoral responses in RMs and to enable isolation of live GC B cells for in vitro culture.
Garnett H. Kelsoe
- Lymphocyte development and antigen-driven diversification of immunoglobulin and T cell antigen receptor genes.
2. The germinal center reaction and mechanisms for clonal selection and self - tolerance. The origins of autoimmunity.
3. Interaction of innate- and adaptive immunity and the role of inflammation in lymphoid organogenesis.
4. The role of secondary V(D)J gene rearrangment in lymphocyte development and malignancies.
5. Mathematical modeling of immune responses, DNA motifs, collaborations in bioinformatics.
6. Humoral immunity to influenza and HIV-1.
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