Human blood Tfr cells are indicators of ongoing humoral activity not fully licensed with suppressive function
Suppressing Sjögren syndrome
T follicular regulatory (Tfr) cells regulate antibody production in the germinal center, yet individuals with the autoimmune disease Sjögren syndrome have increased numbers of circulating Tfr cells compared with healthy individuals. Fonseca et al. compared blood Tfr cells with tissue Tfr cells and found that blood Tfr cells were phenotypically distinct from their tissue counterparts. Moreover, blood Tfr cells did not preferentially suppress humoral responses and had a naïve-like phenotype. These cells were not thymically derived but were generated during germinal center responses, exiting the tissue to enter the blood. These data explain why increased number of blood Tfr cells does not correlate with increased suppression potential and suggest that, instead, increased numbers of blood Tfr cells indicate ongoing humoral activity.
Abstract
Germinal center (GC) responses are controlled by T follicular helper (Tfh) and T follicular regulatory (Tfr) cells and are crucial for the generation of high-affinity antibodies. Although the biology of human circulating and tissue Tfh cells has been established, the relationship between blood and tissue Tfr cells defined as CXCR5+Foxp3+ T cells remains elusive. We found that blood Tfr cells are increased in Sjögren syndrome, an autoimmune disease with ongoing GC reactions, especially in patients with high autoantibody titers, as well as in healthy individuals upon influenza vaccination. Although blood Tfr cells correlated with humoral responses, they lack full B cell–suppressive capacity, despite being able to suppress T cell proliferation. Blood Tfr cells have a naïve-like phenotype, although they are absent from human thymus or cord blood. We found that these cells were generated in peripheral lymphoid tissues before T-B interaction, as they are maintained in B cell–deficient patients. Therefore, blood CXCR5+Foxp3+ T cells in human pathology indicate ongoing humoral activity but are not fully competent circulating Tfr cells.
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Supplementary Material
Summary
Table S1. Clinical characteristics of 25 patients with primary (pSS) and secondary (sSS) Sjögren syndrome.
Fig. S1. Gating strategy for Tfh cells, CXCR5− Treg cells, and Tfr cells in human blood.
Fig. S2. Variation of blood Tfh cells and total Treg cells according to age.
Fig. S3. Sorting strategy for human blood naïve B cells, Tfh cells, CXCR5− Treg cells, and Tfr cells.
Fig. S4. Representative plots of CXCR5− Treg and Tfr cell suppression curves for coculture assay.
Fig. S5. Expression of CD45RO, CD45RA, and CD31 by human blood Tfh and Tfr cells.
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Published In
Science Immunology
Volume 2 | Issue 14
August 2017
August 2017
Copyright
Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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Received: 11 March 2017
Accepted: 29 June 2017
Acknowledgments
We thank A. C. H. Pinto for the recruitment of healthy adult volunteers and for making the diagram. We thank the Instituto Português do Sangue e da Transplantação, the Centro Hospitalar Lisboa Ocidental–Hospital de Santa Cruz, and the Centro Hospitalar Lisboa Norte–Hospital de Santa Maria (Rheumatology, Otorhinolaryngology, and Obstetrics departments) for human samples and collaborations. We thank the Cambridge BioResource staff for help with volunteer recruitment. We thank members of the Cambridge BioResource Scientific Advisory Board and Management Committee for support of our study and the National Institute for Health Research Cambridge Biomedical Research Centre for funding. We acknowledge the participation of all volunteers. We also thank J. Faro for opinions and statistical review. Funding: This study was funded by HMSP-ICT/0034/2013, FAPESP/19906/2014, PTDC/IMI-IMU/7038/2014 research grants, and LISBOA-01-0145-FEDER-007391, projeto cofinanciado pelo FEDER através POR Lisboa 2020–Programa Operacional Regional de Lisboa, do PORTUGAL 2020, e pela Fundação para a Ciência e a Tecnologia. The vaccination study was funded by the European Research Council Starting Grant TWILIGHT (to M.A.L.). W.P. was funded by a Newton International Fellowship from the Royal Society. M.A.L. was funded by the Bioscience and Biotechnology Research Council. Author contributions: V.R.F. designed research, performed experiments, analyzed data, and wrote the paper. A.A.-D. designed research, performed experiments and statistical analysis, and reviewed the paper. A.R.M., F.R., and A.R.P. performed experiments. W.P. performed the vaccination studies. V.C.R. and S.L.d.S. selected SS and BTK-deficient patients, respectively. J.E.F., A.E.S., and M.A.L. designed research and reviewed the paper. L.G. designed research and wrote the paper. Competing interests: The authors declare that they have no competing interests.
Authors
Funding Information
European Research Council: award305784, TWILIGHT
Fundação para a Ciência e a Tecnologia: award305781, HMSP-ICT/0034/2013
Fundação para a Ciência e a Tecnologia: award305782, FAPESP/19906/2014
Fundação para a Ciência e a Tecnologia: award305783, PTDC/IMI-IMU/7038/2014
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