Autoreactive and immunoregulatory T-cell subsets in insulin-dependent diabetes mellitus.
OBJECTIVE
Type I (insulin-dependent) diabetes mellitus is a T-cell mediated autoimmune disease. Several subsets of T-cells, in particular CD4+ and in vivo activate CD45RA+RO+ T-cells, have been shown to be increased at disease onset. The functional implications of these relative increases in CD4 T-cells were investigated.


METHODS
Subsets of T-cells were sorted on the basis of their activation status (CD45RA+ naive cells, CD45RA+RO+ recently activated cells and CD45RO+ memory cells) and stimulated with autoantigens or recall antigen in vitro.


RESULTS
Proliferative responses to tetanus toxoid were primarily or exclusively observed in resting memory T-cells (CD45RO+). Autoimmune T-cell responses were, however, primarily measured in activated T-cells (CD45RA+RO+) in newly diagnosed Type I diabetic patients, whereas those with longer disease duration reacted to autoantigens with memory T-cells (CD45RO+) (p < 0.004). Interestingly, in non-diabetic control subjects not responding to autoantigens in the regular assay, considerable autoreactive T-cell responses were detectable after sorting in the CD45RO+ or CD45RA+RO+ lymphocyte subsets. Remixing these subsets showed that these autoimmune responses in activated cells could be down-modulated by CD45RA+ lymphocytes, whereas resting memory cells appeared unaffected by the suppressive CD45RA subset.


CONCLUSIONS
These results show that autoimmune T-cell responses can be linked to particular subsets which differ depending on clinical status. Furthermore, the CD45RA T-cell subset harbours lymphocytes potentially capable of suppressing autoimmune T-cell responses. The changes in responsiveness to exogenous insulin may help to unravel the mechanism by which isohormonal therapy could prevent the onset of Type I diabetes.
Peterson
L D
LD
Department of Immunohaematology, University Hospital Leiden, The Netherlands.
van der Keur
M
M
de Vries
R R
RR
Roep
B O
BO
D000293:Adolescent; D000818:Animals; D002455:Cell Division; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007328:Insulin / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008297:Male; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D051381:Rats; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D014407:Tumor Cells, Cultured
D007328:Insulin; D017493:Leukocyte Common Antigens; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1