Induction of IL-15 by TCR/CD3 aggregation depends on IFN-gamma and protects against apoptosis of immature thymocytes in vivo.
TCR/CD3 aggregation by injection of anti-CD3 Ab produces T cell activation, release of cytokines such as IFN-gamma, and apoptosis in the cortical region of the thymus. We show that anti-CD3 Ab induces IL-15 mRNA in spleens of wild-type but not IFN-gamma receptor-knock-out (IFN-gammaR KO) mice. The loss of IL-15 mRNA induction in IFN-gammaR KO mice was associated with increased thymocyte apoptosis. Pretreatment of wild-type mice with neutralizing anti-IL-15 Ab increased the anti-CD3-triggered thymocyte apoptosis, thus mimicking the sensitive phenotype of IFN-gammaR KO mice. Inversely, anti-CD3-induced apoptosis in IFN-gammaR KO mice was suppressed by administration of recombinant IL-15. In IFN-gammaR KO mice and in wild-type mice that were treated with anti-IL-15, augmented apoptosis affected mainly CD4+CD8+ immature thymocytes. IL-15 as well as IL-15Ralpha mRNA expression in thymocytes was not increased by anti-CD3. These data demonstrate that systemic IL-15 exerts anti-apoptotic activity on immature T cells and establish a regulatory mechanism whereby TCR/CD3 engagement induces IL-15 expression via an IFN-gamma-dependent pathway. The self-amplifying nature of this IFN-gamma/IL-15 connection may constitute a regulatory pathway in central tolerance to self.
Matthys
P
P
Laboratory of Immunobiology, Rega Institute for Medical Research and Laboratory for Experimental Medicine and Endocrinology (LEGENDO), University of Leuven, Leuven, Belgium. Patrick.Matthys@rega.kuleuven.ac.be
Dooms
H
H
Rottiers
P
P
Mitera
T
T
Overgergh
L
L
Leclercq
G
G
Billiau
A
A
Grooten
J
J
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D017209:Apoptosis; D017252:CD3 Complex / Q000276:immunology; D005434:Flow Cytometry; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology*; D019409:Interleukin-15 / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000276:immunology*; D017634:Self Tolerance; D013601:T-Lymphocytes / Q000276:immunology*
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D019409:Interleukin-15; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D007371:Interferon-gamma