TCR/CD3 mediated stop-signal is decoupled in T-cells from Ctla4 deficient mice.
CTLA-4 is a co-receptor that plays a pivotal role in regulating the threshold for T-cell activation. We recently reported that CTLA-4 ligation can over-ride the stop-signal induced by anti-CD3 ligation [Schneider H, Downey J, Smith A, Zinselmeyer BH, Rush C, Brewer JM, et al. Reversal of the TCR stop-signal by CTLA-4. Science 2006;313:1972]. While these studies compared CTLA-4 positive and negative T-cells from normal mice, little is known regarding the behaviour of T-cells from diseased Ctla4 deficient mice with auto-proliferative disease. In this study, we show that while activated wild-type and Ctla-4-/- T-cells have similar rates of motility, Ctla-4-/- T-cells show a marked resistance to the induction of a stop-signal by anti-CD3 ligation. By contrast, T-cells from normal mice and CD28 deficient mice underwent a normal slowing of motility in response to anti-CD3 ligation. Our findings identify a fundamental difference between normal versus CTLA-4-/- T-cells from diseased mice in the regulation of motility by anti-CD3 ligation. This dysregulation of motility may contribute to the tissue infiltration and the autoimmune disorder observed in Ctla-4-/- mice.
Downey
Jos
J
Cell Signalling Section, Division of Immunology, Department of Pathology, University of Cambridge, Cambridge, UK.
Smith
Andrew
A
Schneider
Helga
H
Hogg
Nancy
N
Rudd
Christopher E
CE
D000818:Animals; D015703:Antigens, CD / Q000276:immunology* / Q000378:metabolism; D000943:Antigens, Differentiation / Q000276:immunology* / Q000378:metabolism; D018106:CD28 Antigens / Q000276:immunology* / Q000378:metabolism; D017252:CD3 Complex / Q000276:immunology* / Q000378:metabolism; D060908:CTLA-4 Antigen; D008213:Lymphocyte Activation; D051379:Mice; D008817:Mice, Mutant Strains; D011948:Receptors, Antigen, T-Cell / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
D015703:Antigens, CD; D000943:Antigens, Differentiation; D018106:CD28 Antigens; D017252:CD3 Complex; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D011948:Receptors, Antigen, T-Cell