Constitutive impaired TCR/CD3-mediated activation of T cells in IDDM patients co-exist with normal co-stimulation pathways.
IDDM is a T cell-mediated autoimmune disease which is paradoxically associated with T cell functional deficiencies. The proliferative response of PBMC under CD3-, Vbeta2-, Vbeta8- and Vbeta7-stimulation was investigated in IDDM and NIDDM patients, non-diabetic first-degree relatives and control subjects. Despite normal surface expression of the TCR/CD3 complex, the TCR/CD3-mediated proliferation of PBMC from IDDM patients was significantly impaired compared to control subjects (P<0.05). This defect was specific for the autoimmune disease, constitutive and not linked to the class II MHC genotype, to metabolic disturbances or to presence of specific autoantibodies. Inefficient activation of T cells was not related to a lower capacity of CD28 to transduce co-stimulative signals because proliferative responses under CD2/CD28 stimulations were similar in IDDM and control groups. The IL-2/IL-2 receptor system was functional because unstimulated PBMC proliferated in response to increasing amounts of IL-2. Nevertheless, despite normal expression of CD25, addition of IL-2 did not normalize the proliferative defect linked to IDDM. In conclusion, excluding a faulty co-stimulation pathway, these results are in favour of a constitutive defect in the CD3/TCR transduction machinery, increasing sensitivity to apoptosis or anergy in T cells from IDDM patients.
Nervi
S
S
Laboratoire de Diabétologie, UPRES-EA 2193, Université de la Méditerranée, Marseille, France.
Atlan-Gepner
C
C
Fossat
C
C
Vialettes
B
B
D000328:Adult; D018106:CD28 Antigens; D017252:CD3 Complex; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D005260:Female; D006801:Humans; D007376:Interleukin-2; D008213:Lymphocyte Activation; D008297:Male; D011948:Receptors, Antigen, T-Cell; D016693:Receptors, Antigen, T-Cell, alpha-beta; D015375:Receptors, Interleukin-2; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*
D018106:CD28 Antigens; D017252:CD3 Complex; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D016693:Receptors, Antigen, T-Cell, alpha-beta; D015375:Receptors, Interleukin-2