A distinct subpopulation of CD25⁻ T-follicular regulatory cells localizes in the germinal centers

T-follicular helper (Tfh) cells differentiate through a multistep process, culminating in germinal center (GC) localized GC-Tfh cells that provide support to GC-B cells. T-follicular regulatory (Tfr) cells have critical roles in the control of Tfh cells and GC formation. Although Tfh-cell differenti...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2017-08, Vol.114 (31), p.E6400-E6409
Main Authors: Wing, James Badger, Kitagawa, Yohko, Locci, Michela, Hume, Hannah, Tay, Christopher, Morita, Takayoshi, Kidani, Yujiro, Matsuda, Kyoko, Inoue, Takeshi, Kurosaki, Tomohiro, Crotty, Shane, Coban, Cevayir, Ohkura, Naganari, Sakaguchi, Shimon
Format: Article
Language:English
Subjects:
Animals
Biological Sciences
Down-Regulation - immunology
Forkhead Transcription Factors - biosynthesis
Germinal Center - cytology
Germinal Center - immunology
Humans
Interleukin-2 Receptor alpha Subunit - biosynthesis
Interleukin-2 Receptor alpha Subunit - genetics
Lymphoid Tissue - cytology
Lymphoid Tissue - immunology
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Knockout
PNAS Plus
Positive Regulatory Domain I-Binding Factor 1 - biosynthesis
Proto-Oncogene Proteins - biosynthesis
Receptors, CXCR5 - biosynthesis
Repressor Proteins - biosynthesis
T-Lymphocytes, Helper-Inducer - immunology
T-Lymphocytes, Regulatory - immunology
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Summary:T-follicular helper (Tfh) cells differentiate through a multistep process, culminating in germinal center (GC) localized GC-Tfh cells that provide support to GC-B cells. T-follicular regulatory (Tfr) cells have critical roles in the control of Tfh cells and GC formation. Although Tfh-cell differentiation is inhibited by IL-2, regulatory T (Treg) cell differentiation and survival depend on it. Here, we describe a CD25⁻ subpopulation within both murine and human PD1⁺CXCR5⁺Foxp3⁺ Tfr cells. It is preferentially located in the GC and can be clearly differentiated from CD25⁺ non–GC-Tfr, Tfh, and effector Treg (eTreg) cells by the expression of a wide range of molecules. In comparison to CD25⁺ Tfr and eTreg cells, CD25⁻ Tfr cells partially down-regulate IL-2–dependent canonical Treg features, but retain suppressive function, while simultaneously upregulating genes associated with Tfh and GC-Tfh cells. We suggest that, similar to Tfh cells, Tfr cells follow a differentiation pathway generating a mature GC-localized subpopulation, CD25⁻ Tfr cells.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1705551114