Dysfunction of T cell receptor AV24AJ18+,BV11+double-negative regulatory natural killer T cells in autoimmune diseases

Objective. We examined the reduction of T cell receptor (TCR) AV24+,BV11+ C D4-,CD8- (double-negative [DN]) natural killer T (NKT) cells in peripheral blood lymphocytes (PBLs) from patients with rheumatoid arthritis (RA), syst emic lupus erythematosus (SLE), systemic sclerosis (SSc), and Sjogren's syn drome (SS) to analyze why NKT cells are selectively reduced in autoimmune d iseases, and to examine whether nonresponse to alpha -galactosylceramide (a lpha -GalCer) is due to an abnormality in the antigen-presenting cells (APC s) or NKT cells. Methods. Peripheral blood from patients with RA (n = 20), SLE (n = 18), SSc (n = 13), and SS (n = 17), as well as from healthy donors (n = 13) and pat ients with Behcet's disease (BD; n = 20), was examined by flow cytometry to determine the number of TCR AV24+,BV11+ DN T cells. PBLs from 10 RA, 10 SL E, 8 SSc, and 9 SS patients, as well as from 7 healthy subjects, were cultu red in vitro with alpha -GalCer, and the number of TCR AV24+,BV11+ DN NKT c ells was estimated. APCs from responder and nonresponder patients were cocu ltured with NKT cells from responder and nonresponder patients. Results. The mean SEM number of TCR AV24+,BV11+ DN NKT cells per ml of whol e blood was found to be 48.8 +/- 10.0 in RA patients, 50.6 +/- 12.9 in SLE patients, 80.8 +/- 30.6 in SSc patients, and 40.0 +/- 11.7 in SS patients, while 290.0 +/- 69.6 and 321.2 +/- 103.4 NKT cells were present in healthy subjects and BD patients, respectively (P < 0.01). Three of 10 RA patients, 5 of 10 SLE patients, 4 of 8 SSc patients, and 6 of 9 SS patients (a total of 18 of 37 patients, or 48.6%) responded to <alpha>-GalCer, indicating th at patients could be divided into two groups: alpha -GalCer responders and nonresponders. In contrast, NKT cells from all healthy subjects proliferate d against alpha -GalCer. APCs from all nonresponder patients were found to function as alpha -GalCer-presenting cells, while NKT cells from nonrespond ers did not expand even in the presence of APCs from normal responders. Conclusion. These findings strongly suggest that patients with autoimmune d iseases can be divided into two groups (alpha -GalCer responders and nonres ponders). They also suggest that the reduced numbers of NKT cells in patien ts with autoimmune diseases may be due to an inadequate amount of alpha -Ga lCer-like natural ligands (i.e., adequate in only 48.6% of patients) for th e induction of NKT cells in vivo, or to a dysfunction in the NKT cells them selves (in 51.4% of patients).