Differential antigen sensitivity and costimulatory requirements in human Th1 and Th2 antigen-specific CD4+ cells with similar TCR avidity.
The differentiation of naive CD4(+) Th cells into Th1 and Th2 phenotypes is influenced by cytokines, concentration of Ag, accessory molecules, and the affinity of the MHC-TCR interaction. To study these factors in human memory T cells, T cell lines with Th1 or Th2 phenotypes specific for the peptide hemagglutinin (HA)(307-319) in the context of DRB1*0401 were established from the peripheral blood of an individual previously vaccinated for influenza virus. Flow cytometric analysis with fluorescent-labeled MHC class II tetramers was used to analyze TCR avidity: the Th2 line bound the HLA-DR*0401-HA(307-319) tetramers with higher mean avidity, although the range of binding avidity largely overlapped with the Th1 line. High-affinity Th1 and Th2 lines were established for further study by FACS sorting. When activated with plate-bound HLA-DR*0401-HA(307-319) monomers, the Th1 line proliferated and produced IFN-gamma without additional costimulation whereas the Th2 line required the addition of soluble anti-CD28 Ab to induce proliferation and IL-5 production, but this requirement could be overcome with high concentrations of plate-bound monomer alone. IL-2 production was dependent on costimulation in both cell lines. These findings demonstrate that upon antigenic rechallenge, Th1 and Th2 cells differ in their response to Ag-specific stimulation. Th2 cells were sensitive to the strength of signal to a greater degree than Th1 cells and required costimulation through CD28 for maximal proliferation. These distinctions between Th1 and Th2 activation are not consistent with a simple avidity model of Ag recognition and indicate both qualitative and quantitative differences in determining cell lineage commitment.
Holzer
Ursula
U
Benaroya Research Institute, Virginia Mason Research Center, Seattle, WA 98101, USA.
Kwok
William W
WW
Nepom
Gerald T
GT
Buckner
Jane Hoyt
JH
D002454:Cell Differentiation / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D019070:Cell Lineage / Q000276:immunology; D002478:Cells, Cultured; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D006389:Hemagglutinins, Viral / Q000276:immunology* / Q000494:pharmacology; D006801:Humans; D007156:Immunologic Memory; D008213:Lymphocyte Activation / Q000276:immunology*; D010446:Peptide Fragments / Q000276:immunology* / Q000494:pharmacology; D011485:Protein Binding / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism*; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism* / Q000821:virology; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism* / Q000821:virology
D018984:Epitopes, T-Lymphocyte; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D006389:Hemagglutinins, Viral; D010446:Peptide Fragments; D016693:Receptors, Antigen, T-Cell, alpha-beta; C081942:influenza hemagglutinin (307-319)