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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Immunol. | doi: 10.3389/fimmu.2018.03178

Residual activatability of circulating Tfh17 predicts humoral response to thymodependent antigens in patients on therapeutic immunosuppression

 Suzan Dahdal1, Carole Saison1,  Martine Valette1, Emmanuel Bachy1,  Nicolas Pallet2, Bruno Lina1, Guillaume Monneret1,  Thierry DEFRANCE3, Emmanuel Morelon1 and  Olivier Thaunat1*
  • 1Hospices Civils de Lyon, France
  • 2Assistance Publique Hopitaux De Paris (AP-HP), France
  • 3UMR5308 Centre International de Recherche en Infectiologie (CIRI), France

The generation of antibodies against protein antigens (such as donor-specific HLA molecules) requires that T follicular helper cells (Tfh) provide help to B cells. Immunosuppressive (IS) armamentarium prevents T cell activation, yet a significant proportion of renal transplant patients develop donor-specific antibodies (DSA), which suggests that IS drugs do not efficiently block their T follicular helper cells.
To test this hypothesis, the number of circulating Tfh, their polarisation profile, and ability to up-regulate i) the costimulatory molecules CD40L and ICOS, and ii) the activation marker CD25, following in vitro stimulation in presence of IS drugs, were compared between 36 renal transplant patients (6-72 months post transplantation) and 9 healthy controls.
IS drugs reduced the number of Tfh1 and 2 but had little impact on Tfh17, which was the dominant subset in transplant patients. Although IS drugs decreased activation-induced expression of costimulatory molecules by Tfh, the impact was highly variable between individuals. Furthermore, 20% of transplant patients displayed normal expression of CD25 on Tfh following in vitro stimulation (i.e. "residual activatability").
To test whether residual activatability of Tfh correlates with antibody response against thymo-dependent antigens we took advantage of the 2015 influenza vaccination campaign, which provided a normalized setting for antigenic stimulation. In line with our hypothesis, responders to influenza vaccine exhibited significantly higher percentage of CD25-expressing Tfh17 after in vitro stimulation. A results that was confirmed retrospectively in 9 transplanted patients at the time of first DSA detection.
We concluded that "residual activatability" of Tfh17 might be used as a non-invasive biomarker to identify transplant patients at higher risk to develop DSA under immunosuppression. If validated in larger studies, this assay might help optimising the prevention of DSA through personalised adaptation of immunosuppressive regimen.

Keywords: Transplantation, Donor-specific antibodies (DSA), T follicular helper (Tfh) cell, biomarkers, Immunosuppression (IS)

Received: 11 Oct 2018; Accepted: 27 Dec 2018.

Edited by:

Geraldo Aleixo Passos, University of São Paulo, Brazil

Reviewed by:

Nuala MOONEY, Centre National de la Recherche Scientifique (CNRS), France
Katja Kotsch, Charité Medical University of Berlin, Germany  

Copyright: © 2018 Dahdal, Saison, Valette, Bachy, Pallet, Lina, Monneret, DEFRANCE, Morelon and Thaunat. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Olivier Thaunat, Hospices Civils de Lyon, Lyon, 69002, Rhône-Alpes, France, olivier.thaunat@chu-lyon.fr