Modulation of CD1d-restricted NKT cell responses by CD4.
CD4+ and CD4- NKT cell populations have been shown to be functionally distinct, but the role of CD4 molecules in NKT cell activation is not clear. Here, we have used human CD1d-restricted NKT cell clones to investigate the contribution of CD4 to NKT cell functional responses. Coligation of CD4 with the TCR/CD3 complex resulted in enhanced cytokine secretion and increased calcium flux by CD4+ NKT cell clones, indicating that CD4 is functionally active in these cells. CD4 blockade specifically inhibited cytokine secretion and proliferation of CD4+ NKT cell clones in response to CD1d+ APCs but did not affect cytotoxicity, suggesting that CD4 preferentially modulates some NKT cell functional responses and not others. Anti-CD4 mAb treatment inhibited NKT cell responses to both MHC class II(+) and MHC class II(-) APCs, indicating that its effect was not due to blocking CD4 binding to MHC class II molecules on APCs. The inhibitory effect of the anti-CD4 mAb also did not require recognition of CD1d by the NKT cell, since calcium flux was reduced in response to anti-CD3 mAb stimulation. Western blot analysis revealed that anti-CD4 treatment resulted in increased phosphorylation of an inhibitory site of p56(lck) (tyrosine 505). Thus, CD4 blockade interferes with the course of CD3-mediated signaling events in NKT cells. These results indicate that CD4 can contribute to NKT cell activation independently of the presence of a CD4-ligand on APCs and suggest that it preferentially modulates cytokine and proliferative responses.
Chen
Xiuxu
X
Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53705, USA.
Wang
Xiaohua
X
Besra
Gurdyal S
GS
Gumperz
Jenny E
JE
D000906:Antibodies / Q000494:pharmacology; D000938:Antigen-Presenting Cells / Q000166:cytology / Q000276:immunology; D018949:Antigens, CD1 / Q000276:immunology*; D055610:Antigens, CD1d; D015153:Blotting, Western; D017252:CD3 Complex / Q000276:immunology; D015704:CD4 Antigens / Q000276:immunology*; D002118:Calcium / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002999:Clone Cells; D003432:Cross-Linking Reagents / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006801:Humans; D007694:Killer Cells, Natural / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D019000:Phosphotyrosine / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D000906:Antibodies; D018949:Antigens, CD1; D055610:Antigens, CD1d; C526877:CD1D protein, human; D017252:CD3 Complex; D015704:CD4 Antigens; D003432:Cross-Linking Reagents; D016207:Cytokines; D000949:Histocompatibility Antigens Class II; D019000:Phosphotyrosine; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D002118:Calcium