Interferon alpha increases the frequency of interferon gamma-producing human CD4+ T cells.
An increased ratio of T helper type 2 (Th2)- vs Th1-like cells contributes to the immune dysregulation in allergic disease situations and in many chronic infections, including AIDS. Th2-type immune responses are characterized by Th cells that produce increased levels of interleukin-4 (IL-4) and decreased levels of interferon gamma (IFN-gamma). The induction of either a Th1- or a Th2-like phenotype may be critically controlled by the antigen-presenting cells and their cytokines, e.g., IFN-alpha. In this study we have determined the frequencies of potential IL-4- and/or IFN-gamma-producing T cells in the peripheral blood of randomly selected healthy individuals, and analyzed whether IFN-alpha controls IL-4 and/or IFN-gamma production. Purified CD4+ or CD8+ T cells were stimulated for 24 h via the T cell receptor/CD3 complex in the presence or absence of IFN-alpha, and single IL-4- and IFN-gamma-secreting cells were detected in enzyme-linked immunospot assays. In the absence of IFN-alpha, CD4 cells produced IFN-gamma at frequencies of 1:50-300, and produced IL-4 at frequencies of 1:110-<1:100,000. Addition of IFN-alpha during the activation of CD4 cells increased the levels of IFN-gamma mRNA. As a consequence, the numbers of IFN-gamma-producing CD4 cells and the amounts of secreted IFN-gamma increased 10-fold. In contrast, IFN-alpha did not increase the frequency of IL-4-secreting CD4 cells. In the absence of IFN-alpha, addition of exogenous IL-4 to cultures of CD4 cells suppressed IFN-gamma secretion by 70%. However, in the presence of IFN-alpha, IL-4 did not display any suppressive effect. Compared with CD4 cells, CD8 cells produced IFN-gamma more frequently (1:5-10) but IL-4 less frequently (1:5,300 to < 1:100,000). IFN-alpha did not display any effect on the frequency of either IFN-gamma or IL-4 production by CD8 cells. Taken together the results indicate that IFN-alpha increases the frequency of IFN-gamma-secreting CD4 Th cells and antagonizes the suppressive effect of IL-4 on IFN-gamma production. As a consequence, IFN-alpha may favor the induction and maintenance of Th1-like cells and thereby counteract Th2-driven allergic immune responses.
Brinkmann
V
V
Allergy/Immunology, Pharmaceuticals Research Division, Ciba-Geigy Limited, Basel, Switzerland.
Geiger
T
T
Alkan
S
S
Heusser
C H
CH
D000163:Acquired Immunodeficiency Syndrome / Q000276:immunology; D015704:CD4 Antigens / Q000276:immunology*; D002469:Cell Separation / Q000379:methods; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007370:Interferon Type I / Q000494:pharmacology*; D007371:Interferon-gamma / Q000096:biosynthesis*; D015847:Interleukin-4 / Q000096:biosynthesis; D007700:Kinetics; D012333:RNA, Messenger / Q000096:biosynthesis; D011994:Recombinant Proteins; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology*
D015704:CD4 Antigens; D007370:Interferon Type I; D012333:RNA, Messenger; D011994:Recombinant Proteins; D015847:Interleukin-4; D007371:Interferon-gamma