Blocking inducible co-stimulator in the absence of CD28 impairs Th1 and CD25+ regulatory T cells in murine colitis.
Several autoimmune disease models depend on an imbalance in the activation of aggressor T(h)1 and CD4(+)CD25(+) regulatory T (T(reg)) cells. Here we compare the requirement for signals through the co-stimulatory molecules CD28 and inducible co-stimulator (ICOS) in chronic murine colitis, a model for inflammatory bowel disease. We used a colitis model in which disease-causing CD45RB(hi) T cells alone or in combination with CD4(+)CD25(+) T cells from either CD28-deficient or wild-type donors were transferred into T cell-deficient animals, half of which were treated with ICOS-blocking reagents. Blocking ICOS on the surface of CD28-deficient T(h)1 cells abrogated development of colitis, whereas blocking CD28 or ICOS alone had little to no effect on disease induction. In contrast to T(h)1 cells, regulatory T cell functioning depended mostly on CD28 signaling with only a minor contribution for ICOS. We conclude that CD28 and ICOS collaborate to development of murine colitis by aggressor T(h)1 cells, and that CD28 is required for T(reg) cells, which should caution against the use of CD28-blocking reagents in inflammatory bowel disease.
de Jong
Ype P
YP
Division of Immunology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
Rietdijk
Svend T
ST
Faubion
William A
WA
Abadia-Molina
Ana C
AC
Clarke
Kareem
K
Mizoguchi
Emiko
E
Tian
Jane
J
Delaney
Tracy
T
Manning
Stephen
S
Gutierrez-Ramos
Jose-Carlos
JC
Bhan
Atul K
AK
Coyle
Anthony J
AJ
Terhorst
Cox
C
D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology*; D018122:B7-1 Antigen / Q000276:immunology; D018106:CD28 Antigens / Q000276:immunology*; D015704:CD4 Antigens / Q000276:immunology*; D003092:Colitis / Q000276:immunology / Q000473:pathology; D016207:Cytokines / Q000096:biosynthesis; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein; D015212:Inflammatory Bowel Diseases / Q000276:immunology*; D017493:Leukocyte Common Antigens / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology*
D000945:Antigens, Differentiation, T-Lymphocyte; D018122:B7-1 Antigen; D018106:CD28 Antigens; D015704:CD4 Antigens; D016207:Cytokines; C556694:Icos protein, mouse; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein; D017493:Leukocyte Common Antigens