ICOS ligand costimulation is required for T-cell encephalitogenicity.
The interaction of ICOS with its ligand on APC provides a costimulatory signal to previously activated T-cells. In these studies, we blocked the ICOS:ICOS ligand interaction with ICOS-Ig during the in vitro activation of MBP-reactive transgenic CD4(+) T-cells. The presence of ICOS-Ig in these cultures inhibited the ability of the transgenic T-cells to transfer EAE, although they entered the brains of the recipient mice. ICOS-Ig increased apoptosis in the transgenic T-cells, especially in the memory population. This enhanced apoptosis was accompanied by an increase in the BAX/BCL-2 mRNA ratio. ICOS-Ig did not prevent IL2 production, demonstrating that IL-2 production is ICOS ligand independent. IFN-gamma and IL-10 production by the transgenic T-cells, however, was suppressed. Finally, ICOS-Ig injection into mice after the first signs of EAE ameliorated clinical disease. Therefore, ICOSL provides a signal distinct from CD28 costimulation that is required for the activation and viability of encephalitogenic T-cells.
Sporici
R A
RA
Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Beswick
R L
RL
von Allmen
C
C
Rumbley
C A
CA
Hayden-Ledbetter
M
M
Ledbetter
J A
JA
Perrin
P J
PJ
D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000502:physiology*; D018106:CD28 Antigens / Q000502:physiology; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000209:etiology*; D060889:Inducible T-Cell Co-Stimulator Protein; D008024:Ligands; D008213:Lymphocyte Activation; D051379:Mice; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology*
D000945:Antigens, Differentiation, T-Lymphocyte; D018106:CD28 Antigens; D016207:Cytokines; C556694:Icos protein, mouse; D060889:Inducible T-Cell Co-Stimulator Protein; D008024:Ligands; D019253:Proto-Oncogene Proteins c-bcl-2