Restricted BV gene usage by factor VIII-reactive CD4+ T cells in inhibitor-positive patients with severe hemophilia A.
In the present study, we have analyzed the T cell receptor (TCR) repertoires of CD4+ T cells isolated from peripheral blood of 10 inhibitor-positive patients with severe hemophilia A. The distribution of complementarity determining region (CDR3) lengths of the beta chain of the TCRs was analyzed by spectratyping prior to and following in vitro stimulation of the cells with human factor VIII (FVIII). The repertoires of CD4+ T cells of patients were perturbed when compared to those of healthy blood donors. The perturbations of T cell repertoires were heterogeneous among patients with respect to the number and the nature of V-beta (BV) families that exhibited expansion following incubation with FVIII. Some patients showed alterations in one or two BV families, others exhibited more perturbed repertoires affecting 5 to 8 of the 14 BV families tested. Alterations of BV2, BV5 and/or BV9 were consistently found after incubation of CD4+ T cells in the presence of FVIII in 80% of the patients. These findings indicate that the presence of FVIII inhibitors in patients with severe hemophilia A is associated with measurable perturbations of the CD4+ T cell repertoire that results from oligoclonal expansion of FVIII-specific cells and may be relevant for the design of strategies aimed at modulating the anti-FVIII immune responses by T cell-targeted therapy
Misra
Namita
N
INSERM U430, Université Pierre et Marie Curie, Centre de Recherches Biomedicales des Cordeliers, Rue de l'Ecole de Médecine, 75006 Paris, France. namita.misra@u430.bhdc.jussieu.fr
Bayry
Jagadeesh
J
Pashov
Anastas
A
Kaveri
Srini V
SV
D'Oiron
Roseline
R
Stieltjes
Natalie
N
Roussel-Robert
Valeri
V
Kazatchkine
Michel D
MD
Boyer
Olivier
O
Lacroix-Desmazes
Sébastien
S
D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D002999:Clone Cells / Q000276:immunology; D022801:Complementarity Determining Regions; D005169:Factor VIII / Q000276:immunology*; D019674:Genes, T-Cell Receptor beta / Q000276:immunology*; D006467:Hemophilia A / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D008875:Middle Aged
D022801:Complementarity Determining Regions; D005169:Factor VIII