Signal transduction in lymphocyte activation through crosslinking of HLA class I molecules.
The inhibitory effect of anti-HLA class I monoclonal antibodies on lymphocyte proliferation has been well documented. However, recent data suggest that anti-HLA class I monoclonal antibodies can enhance lymphocyte proliferation via both anti-CD3-induced (1,2) and anti-CD2-induced (3) activation pathways. Here we demonstrate that both inhibition and activation can be regulated by the degree of aggregation of HLA class I antigens. Crosslinking of monoclonal antibodies specific for HLA-A, HLA-B, or monomorphic determinants (using anti-IgG2 and/or anti-Ig kappa "second step" monoclonal antibodies) increased the capacity of anti-HLA class I monoclonal antibodies to inhibit phytohemagglutinin-induced proliferation. However, the cytosolic free calcium concentration was increased in CD4+ cells, CD8+ cells, B cells, and CD16+ cells when anti-HLA class I monoclonal antibodies were crosslinked, suggesting that an activation signal was generated by aggregation of the corresponding antigens. Indeed, inositol 1,4,5-trisphosphate could be detected in peripheral blood lymphocytes following crosslinking of anti-HLA class I monoclonal antibodies. Class I aggregation also induced proliferation of peripheral blood mononuclear cells in the presence of submitogenic doses of phorbol 12-myristate 13-acetate. Strong conditions of crosslinking (monomorphic monoclonal antibody plus both anti-IgG2 and anti-Ig kappa) induced CD25 expression and responsiveness to recombinant interleukin 2. Our results suggest that aggregation of HLA class I antigens primed cells to become activated in the presence of progression signals including phorbol 12-myristate 13-acetate, recombinant interleukin 2, or anti-CD5 plus anti-CD28 monoclonal antibodies.
Gilliland
L K
LK
ONCOGEN, Seattle, Washington 98121.
Norris
N A
NA
Grosmaire
L S
LS
Ferrone
S
S
Gladstone
P
P
Ledbetter
J A
JA
D000911:Antibodies, Monoclonal; D000943:Antigens, Differentiation; D018956:CD5 Antigens; D002118:Calcium / Q000378:metabolism; D003432:Cross-Linking Reagents; D006680:HLA Antigens; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate; D007295:Inositol Phosphates / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D008214:Lymphocytes / Q000145:classification / Q000276:immunology / Q000378:metabolism; D015375:Receptors, Interleukin-2; D015398:Signal Transduction / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D000943:Antigens, Differentiation; D018956:CD5 Antigens; D003432:Cross-Linking Reagents; D006680:HLA Antigens; D007295:Inositol Phosphates; D015375:Receptors, Interleukin-2; D015544:Inositol 1,4,5-Trisphosphate; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium