Germinal Center Formation Controlled by Balancing Between Follicular Helper T Cells and Follicular Regulatory T Cells

Hong-Jai Park; Do-Hyun Kim; Je-Min Choi

doi:10.7599/hmr.2013.33.1.10

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Park, Kim, and Choi: Germinal Center Formation Controlled by Balancing Between Follicular Helper T Cells and Follicular Regulatory T Cells

Review Article

Hanyang Medical Reviews

Hanyang Medical Reviews 2013; 33(1): 10-16.

Published online: 27 February 2013

DOI: https://doi.org/10.7599/hmr.2013.33.1.10

Germinal Center Formation Controlled by Balancing Between Follicular Helper T Cells and Follicular Regulatory T Cells

Hong-Jai Park, Do-Hyun Kim, Je-Min Choi

Department of Life Science, College of Natural Sciences, Hanyang University, Seoul, Korea.

Correspondence to: Je-Min Choi. Department of Life Science, College of Natural Sciences, Hanyang University, 531-ho, 222, Wangsimni-ro, Seongdong-gu, Seoul 133-791, Korea. Tel: +82-2-2220-4765, Fax: +82-2-2299-3495, jeminchoi@hanyang.ac.kr

Received 5 December 2012 Revised 31 January 2013 Accepted 8 February 2013

(open-access):

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Follicular helper T cells (Tfh) play a significant role in providing T cell help to B cells during the germinal center reaction, where somatic hypermutation, affinity maturation, isotype class switching, and the differentiation of memory B cells and long-lived plasma cells occur. Antigen-specific T cells with IL-6 and IL-21 upregulate CXCR5, which is required for the migration of T cells into B cell follicles, where these T cells mature into Tfh. The surface markers including PD-1, ICOS, and CD40L play a significant role in providing T cell help to B cells. The upregulation of transcription factor Bcl-6 induces the expression of CXCR5, which is an important factor for Tfh differentiation, by inhibiting the expression of other lineage-specific transcription factors such as T-bet, GATA3, and RORγt. Surprisingly, recent evidence suggests that CD4 T cells already committed to Th1, Th2, and Th17 cells obtain flexibility in their differentiation programs by downregulating T-bet, GATA3, and RORγt, upregulating Bcl-6 and thus convert into Tfh. Limiting the numbers of Tfh within germinal centers is important in the regulation of the autoantibody production that is central to autoimmune diseases. Recently, it was revealed that the germinal center reaction and the size of the Tfh population are also regulated by thymus-derived follicular regulatory T cells (Tfr) expressing CXCR5 and Foxp3. Dysregulation of Tfh appears to be a pathogenic cause of autoimmune disease suggesting that tight regulation of Tfh and germinal center reaction by Tfr is essential for maintaining immune tolerance. Therefore, the balance between Tfh and Tfr appears to be a critical peripheral tolerance mechanism that can inhibit autoimmune disorders.

Keywords: T-Lymphocytes, Helper-Inducer, T-Lymphocytes, Regulatory, Germinal Center, Autoimmunity

Figures and Tables

Fig. 1

Germinal center formation controlled by Tfh and Tfr. Naïve T cells interact with Ag-presenting DC and differentiate into specific helper T cell subsets upon TCR stimulation under specific cytokine environment. IL-6 and IL-21 activate Bcl-6 expression which determines T cells fate to Tfh by expression of CXCR5. Tfh migrates to B cell area via CXCL13-CXCR5 interaction, and they contribute germinal center (GC) formation with follicular dendritic cells (fDC). Tfh provides T cell help to GC B cell induces isotype class-switching, somatic hypermutation, and affinity maturation via IL-21 and IL-4. For GC formation, interaction between Tfh and B cells essentially mediate through ICOS-ICOSL and CD40-CD40L. GC B cell will differentiate into plasma cells and memory B cells which is necessary for humoral immune responses. Tfh-mediated GC formation is regulated by thymic nTreg-derived Tfr cells expressing Foxp3 and CXCR5. Tfr migrate to B cell area to control Tfh and GC B cell responses which regulate GC formation and humoral response to inhibit autoimmune diseases.

ACKNOWLEDGEMENTS

This work is supported by Basic Science Research Program through National Research Foundation of Korea grants (2012-0003073 and 2012-0007210). The authors declare no competing financial interests.

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