Short cytoplasmic SDYMNM segment of CD28 is sufficient to convert CTLA-4 to a positive signaling receptor.
CD28 and cytotoxic T-lymphocyte antigen (CTLA)-4 are key coreceptors on the surface of T cells that have opposing effects on T cell activation. Although CD28 enhances proliferation, CTLA-4 markedly inhibits the activation process. These opposing roles are particularly surprising given the structural similarity of the cytoplasmic residues of the two receptors. These include the related CD28(SDYMNM) and CTLA-4(GVYVKM) motifs. In this study, we have directly addressed whether these related motifs may play different roles in the activation process by swapping the CTLA-4(GVYVKM) motif with the CD28(SDYMNM) motif. Remarkably, stable transfectants of the T cell hybridoma DC27.10 showed that substitution of CTLA-4(GVYVKM) was sufficient to convert CTLA-4 from a negative signaling coreceptor to a positive CD28-like coreceptor. CD28(SDYMNM) is therefore sufficient to convey positive signals within CTLA-4. These results demonstrate that CD28(SDYMNM) and CTLA-4(GVYVKM) motifs contain sufficient information to distinguish positive versus negative coreceptor signaling in T cells.
Yin
Li
L
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Schneider
Helga
H
Rudd
Christopher E
CE
D000069594:Abatacept; D020816:Amino Acid Motifs / Q000502:physiology; D000595:Amino Acid Sequence / Q000502:physiology; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D018106:CD28 Antigens / Q000737:chemistry / Q000502:physiology*; D060908:CTLA-4 Antigen; D002460:Cell Line; D003593:Cytoplasm; D006801:Humans; D018796:Immunoconjugates; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism; D014162:Transfection
D015703:Antigens, CD; D000943:Antigens, Differentiation; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D011993:Recombinant Fusion Proteins; D000069594:Abatacept; D019869:Phosphatidylinositol 3-Kinases