Exaggerated follicular helper T-cell responses in patients with LRBA deficiency caused by failure of CTLA4-mediated regulation - 07/03/18
Abstract |
Background |
LPS-responsive beige-like anchor protein (LRBA) and cytotoxic T lymphocyte–associated antigen 4 (CTLA4) deficiencies give rise to overlapping phenotypes of immune dysregulation and autoimmunity, with dramatically increased frequencies of circulating follicular helper T (cTFH) cells.
Objective |
We sought to determine the mechanisms of cTFH cell dysregulation in patients with LRBA deficiency and the utility of monitoring cTFH cells as a correlate of clinical response to CTLA4-Ig therapy.
Methods |
cTFH cells and other lymphocyte subpopulations were characterized. Functional analyses included in vitro follicular helper T (TFH) cell differentiation and cTFH/naive B-cell cocultures. Serum soluble IL-2 receptor α chain levels and in vitro immunoglobulin production by cultured B cells were quantified by using ELISA.
Results |
cTFH cell frequencies in patients with LRBA or CTLA4 deficiency sharply decreased with CTLA4-Ig therapy in parallel with other markers of immune dysregulation, including soluble IL-2 receptor α chain, CD45RO+CD4+ effector T cells, and autoantibodies, and this was predictive of favorable clinical responses. cTFH cells in patients with LRBA deficiency were biased toward a TH1-like cell phenotype, which was partially reversed by CTLA4-Ig therapy. LRBA-sufficient but not LRBA-deficient regulatory T cells suppressed in vitro TFH cell differentiation in a CTLA4-dependent manner. LRBA-deficient TFH cells supported in vitro antibody production by naive LRBA-sufficient B cells.
Conclusions |
cTFH cell dysregulation in patients with LRBA deficiency reflects impaired control of TFH cell differentiation because of profoundly decreased CTLA4 expression on regulatory T cells and probably contributes to autoimmunity in patients with this disease. Serial monitoring of cTFH cell frequencies is highly useful in gauging the clinical response of LRBA-deficient patients to CTLA4-Ig therapy.
Le texte complet de cet article est disponible en PDF.Graphical abstract |
Key words : Autoantibodies, LPS-responsive beige-like anchor, cytotoxic T lymphocyte–associated antigen 4, regulatory T cells, follicular helper T cells, follicular regulatory T cells
Abbreviations used : cTFH, CTLA4, FOXP3, ICOS, IPEX, iTFH, IVIG, LRBA, PD-1, sCD25, SLE, TFH, TFR, Treg, WES
Plan
| Supported by National Institutes of Health grants 5R01AI065617 (to T.A.C.) and 4R01AI100315 (to R.S.G.) and a grant from the Scientific and Technological Research Council of Turkey (1059B191300622; to S.K.). |
|
| Disclosure of potential conflict of interest: J. Chou is employed by Boston Children's Hospital, and her institution received National Institutes of Health (NIH) grants for other works. C. D. Platt received NIH grant K12 HD052896-10 for other works. M. Jordan received consultancy fees from Bristol Myers. T. A. Chatila's institution received NIH grant 5R01AI065617 for this work. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 141 - N° 3
P. 1050 - mars 2018 Retour au numéro
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