title: Perforin-dependent cytotoxic activity and lymphokine secretion by CD4+ T cells are regulated by CD8+ T cells.
abstract: Factors influencing the development of CD4+ T cell subpopulations with differing lymphokine profiles are well established. However, CD4+ cells can show both perforin- and Fas ligand-dependent cytotoxicity, and little is known about conditions favoring the development of these effector activities. We now report that CD8+ cells regulate the development of perforin-dependent cytotoxicity in CD4+ cells. CD4+ cells activated in either the presence or absence of CD8+ cells developed Fas ligand-dependent cytotoxic activity. However, CD4+ cells developed perforin-dependent cytotoxicity only in the absence of activated CD8+ cells. CD8+ cells also inhibited the development of IL-4-secreting CD4+ cells; however, there was no correlation between the expression of perforin-dependent cytotoxic activity and the ability to secrete IL-4, and perforin-dependent cytotoxic CD4+ cells represented only 10% of isolated clones. This suggests that the two characteristics are expressed in different CD4+ subsets and might be regulated by distinct effects of the CD8+ cells. In keeping with this, regulation of the lymphokine profile of CD4+ cells by CD8+ cells was consistent with mediation by IFN-gamma, but only when delivered at high concentrations requiring close proximity of the cells. In contrast, regulation of perforin-dependent cytotoxic activity of CD4+ cells by CD8+ cells seemed inconsistent with an IFN-gamma-dependent mechanism, suggesting either direct cell contact or close proximity to allow delivery of an unidentified soluble factor. The characteristics of perforin-dependent CD4+ CTL and their regulation by activated CD8+ cells suggest that they represent a previously unrecognized subpopulation that plays a defensive role when a CD8+ cell response is absent.
authors.affiliation: Beirne B. Carter Center for Immunology Research and Department of Microbiology, University of Virginia Health Sciences Center, Charlottesville 22908, USA.
authors.forename: N S
authors.initials: NS
authors.lastname: Williams
authors.forename: V H
authors.initials: VH
authors.lastname: Engelhard
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002450:Cell Communication; D002454:Cell Differentiation; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic; D053222:Fas Ligand Protein; D007371:Interferon-gamma / Q000502:physiology; D008213:Lymphocyte Activation; D008222:Lymphokines / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology; D001613:beta 2-Microglobulin / Q000172:deficiency / Q000502:physiology; D019014:fas Receptor / Q000276:immunology
chemical_list: D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008222:Lymphokines; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D001613:beta 2-Microglobulin; D019014:fas Receptor; D054353:Perforin; D007371:Interferon-gamma