2B4 (CD244) induced by selective CD28 blockade functionally regulates allograft-specific CD8+ T cell responses.
Mounting evidence in models of both autoimmunity and chronic viral infection suggests that the outcome of T cell activation is critically impacted by the constellation of co-stimulatory and co-inhibitory receptors expressed on the cell surface. Here, we identified a critical role for the co-inhibitory SLAM family member 2B4 (CD244) in attenuating primary antigen-specific CD8(+) T cell responses in the presence of immune modulation with selective CD28 blockade. Our results reveal a specific up-regulation of 2B4 on antigen-specific CD8(+) T cells in animals in which CD28 signaling was blocked. However, 2B4 up-regulation was not observed in animals treated with CTLA-4 Ig (abatacept) or CD28 blockade in the presence of anti-CTLA-4 mAb. 2B4 up-regulation after CD28 blockade was functionally significant, as the inhibitory impact of CD28 blockade was diminished when antigen-specific CD8(+) T cells were deficient in 2B4. In contrast, 2B4 deficiency had no effect on CD8(+) T cell responses during unmodified rejection or in the presence of CTLA-4 Ig. We conclude that blockade of CD28 signals in the presence of preserved CTLA-4 signals results in the unique up-regulation of 2B4 on primary CD8(+) effectors, and that this 2B4 expression plays a critical functional role in controlling antigen-specific CD8(+) T cell responses.
Emory Transplant Center and Department of Surgery, Emory University, Atlanta, GA 30322.
Danya
D
Liu
Scott M
SM
Krummey
I Raul
IR
Badell
Maylene
M
Wagener
Lumelle A
LA
Schneeweis
Dawn K
DK
Stetsko
Suzanne J
SJ
Suchard
Steven G
SG
Nadler
Mandy L
ML
Ford
D000069594:Abatacept; D064591:Allografts; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D015703:Antigens, CD / Q000096:biosynthesis* / Q000235:genetics; D060890:B7-H1 Antigen / Q000378:metabolism; D018106:CD28 Antigens / Q000037:antagonists & inhibitors*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors; D006085:Graft Survival / Q000276:immunology; D018796:Immunoconjugates / Q000008:administration & dosage; D060889:Inducible T-Cell Co-Stimulator Protein / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018448:Models, Immunological; D011971:Receptors, Immunologic / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction / Q000276:immunology; D000071176:Signaling Lymphocytic Activation Molecule Family; D016038:Skin Transplantation; D015854:Up-Regulation
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D060890:B7-H1 Antigen; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C490007:Cd244a protein, mouse; C498919:Cd274 protein, mouse; C556694:Icos protein, mouse; D018796:Immunoconjugates; D060889:Inducible T-Cell Co-Stimulator Protein; D011971:Receptors, Immunologic; D000071176:Signaling Lymphocytic Activation Molecule Family; D000069594:Abatacept