TY - JOUR
T1 - Ganglioside modulation of CD4 does not block T‐helper cell function as compared to antagonism by anti‐CD4 antibody
AU - Morrison, William J.
AU - Offner, Halina
AU - Vandenbark, Arthur A.
PY - 1992
Y1 - 1992
N2 - Gangliosides (GM1) modulate CD4 from the surface of T‐helper lymphocytes and have been shown to block CD4‐mediated HIV‐1 infection in vitro. However, the effects of GM1 on CD4 are neutralized in the presence of serum. We sought to make a GM1 derivative which would resist serum neutralization and to determine whether modulation of CD4 by GM1 would affect T‐helper lymphocyte function. Study of GM1 and GM1‐derivatives in the presence of serum indicated that the active conformation involves intact sialic acid hydroxyl groups and intermolecular ganglioside interactions. All chemical modifications directed toward the sialic acid moiety reduced the ability of GM1 to modulate CD4. Elution profiles of GM1 in the presence and absence of albumin indicate that the active form of GM1 is represented by micelles that are disrupted by albumin. Function studies show that CD4 T‐helper cells made CD− by GM1 treatment continued to proliferate in culture and recognize antigen (Ag) through the T cell receptor (TcR). Moreover, T‐helper cell mediated inflammation assessed by Ag‐specific, delayed type hypersensitivity (DTH) was enhanced after passive transfer of GMl‐treated T‐helper cells to naive animals. In comparison, CD4 blockade by anti‐CD4 antibody decreased Ag‐stimulated T‐helper cell proliferation and DTH reactions. These results demonstrate that (1) CD4 modulation involves an active conformation that arises from sialic acid effector molecules organized by micellar GM1 conformations; and (2) the mechanism by which GM1 modulates CD4 is different from CD4 antagonism seen with anti‐CD4 antibody treatment. © 1992 Wiley‐Liss, Inc.
AB - Gangliosides (GM1) modulate CD4 from the surface of T‐helper lymphocytes and have been shown to block CD4‐mediated HIV‐1 infection in vitro. However, the effects of GM1 on CD4 are neutralized in the presence of serum. We sought to make a GM1 derivative which would resist serum neutralization and to determine whether modulation of CD4 by GM1 would affect T‐helper lymphocyte function. Study of GM1 and GM1‐derivatives in the presence of serum indicated that the active conformation involves intact sialic acid hydroxyl groups and intermolecular ganglioside interactions. All chemical modifications directed toward the sialic acid moiety reduced the ability of GM1 to modulate CD4. Elution profiles of GM1 in the presence and absence of albumin indicate that the active form of GM1 is represented by micelles that are disrupted by albumin. Function studies show that CD4 T‐helper cells made CD− by GM1 treatment continued to proliferate in culture and recognize antigen (Ag) through the T cell receptor (TcR). Moreover, T‐helper cell mediated inflammation assessed by Ag‐specific, delayed type hypersensitivity (DTH) was enhanced after passive transfer of GMl‐treated T‐helper cells to naive animals. In comparison, CD4 blockade by anti‐CD4 antibody decreased Ag‐stimulated T‐helper cell proliferation and DTH reactions. These results demonstrate that (1) CD4 modulation involves an active conformation that arises from sialic acid effector molecules organized by micellar GM1 conformations; and (2) the mechanism by which GM1 modulates CD4 is different from CD4 antagonism seen with anti‐CD4 antibody treatment. © 1992 Wiley‐Liss, Inc.
KW - CD4 molecule
KW - T‐helper cells
KW - gangliosides
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U2 - 10.1002/ddr.430250406
DO - 10.1002/ddr.430250406
M3 - Article
AN - SCOPUS:0026588962
SN - 0272-4391
VL - 25
SP - 315
EP - 323
JO - Drug Development Research
JF - Drug Development Research
IS - 4
ER -