Interleukin-12/T cell stimulating factor, a cytokine with multiple effects on T helper type 1 (Th1) but not on Th2 cells (original) (raw)
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European Journal of Immunology, 1993
Antigen-presenting human T cells and antigen-presenting B cells induce a similar cytokine profile in specific T cell clones* One of the factors that may influence the cytokine secretion profile of aTcell is the antigen-presenting cefi (APC). Since-activated human-T cells have been described to express major histocompatibility complex (MHC) class 11 molecules as well as costimulatory molecules for Tcell activation, like e.g. ICAM-1, LFA-3 and B7, they might play a role as APC and be involved in the regulation of T-Tcell interactions.To define further the role of Tcells as APC we tested their capacity to induce proliferation and cytokine production in peptide-or allospecific T cell clones and compared it with conventional APC, like B lymphoblasts (B-LCL) or HTLV-1-transformed T cells, or with non-classical APC, like activated keratinocytes or eosinophils. CD4+, DP-restricted T cell clones specific for a tetanus toxin peptide (amino acids 947-967) and CD4+, DR-restricted allospecific T cell clones produced interleukin (1L)-2, IL-4, tumor necrosis factor-a and interferon-y (IFN-y) after phorbol 12-myristate 13-acetate and ionomycin stimulation and a more restricted cytokine pattern after antigen stimulation. Dose-response curves revealed that the antigen-presenting capacity of activated, MHC class II+, B7+ Tcells was comparable to the one of B-LCL. Both APC induced the same cytokine profile in the T cell clones despite a weaker proliferative response with Tcells as APC. Suboptimal stimulations resulted in a lower IFN-y/IL-4 ratio. Cytokine-treated, MHC class 11+ keratinocytes and eosinophils differed in the expression of adhesion molecules and their capacity to restimulate T cell clones. The strongly ICAM-1-positive keratinocytes induced rather high cytokine levels. In contrast, eosinophils, which express only low densities of MHC class I1 and no or only low levels of adhesion molecules (B7, ICAM-1 and LFA3), provided a reduced signal resulting in a diminished IFN-yhL-4 ratio. We conclude that non-classical APC differ in their capacity to restimulate T cell clones, whereby the intensity of MHC class I1 and adhesion molecules (B7, ICAM-1) expressed seems to determine the efficacy of this presentation.
Cytokine Transcriptional Events during Helper T Cell Subset Differentiation
1996
The molecular basis for changes in cytokine expression during T helper (Th) cell subset differentiation is not well understood. We have characterized transcriptional events related to cytokine gene expression in populations of naive T cell receptor-transgenic T cells as they are driven in vitro toward Thl or Th2 phenotypes by interleukin (IL)-12 or IL-4 treatment, respectively. Quantitative reverse transcriptase-polymerase chain reaction analysis of cytokine transcripts indicates that interferon (IFN) ~/, IL-4, and IL-2 mRNA are expressed with distinct kinetics after naive T cells are stimulated with antigen and either IL-4 or IL-12. IFN-~/mR.NA appears as early as 6 h m IL-12-treated cultures, IL-4 appears only after 48 h in lL-4--treated cultures, and IL-2 is equivalently expressed in both types of cultures. Analyses were performed to determine if there were any differences in activation oflL-2 or IL-4 transcription factors that accompanied Thl versus Th2 differentiation. These studies demonstrated that signal transducer and activator of transcription 6 (STAT6) binds to a sequence in the IL-4 promoter and that this STAT6-binding site can support IL-4--dependent transcription of a linked heterologous promoter. Prolonged activation of STAT6 is characteristic of populations undergoing Th2 differentiation. Furthermore, STAT6 is activated in an autocrine manner when differentiated Th2 populations are stimulated by antigen receptor ligation. Thl populations derived from IL-12 plus antigen treatment of naive T cells remain responsxve to IL-4 as indicated by induction of STAT6 and IL-4 mRNA. These data indicate that Thl and Th2 differentiation represents the combination of different, apparently independently regulated transcriptional events. Furthermore, among transcription factors that bind to the IL-4 or IL-2 promoters, STAT6 is the one whose activation distinguishes Th2 versus Thl development.
Biochemical and Biophysical Research Communications, 2009
In order to fully understand T cell-mediated immunity, the mechanisms that regulate clonal expansion and cytokine production by CD4 + antigen-specific effector T cells in response to a wide range of antigenic stimulation needs clarification. For this purpose, panels of antigen-specific CD4 + T cell clones with different thresholds for antigen-induced proliferation were generated by repeated stimulation with high-or low-dose antigen. Differences in antigen sensitivities did not correlate with expression of TCR, CD4, adhesion or costimulatory molecules. There was no significant difference in antigen-dependent cytokine production by TG40 cells transfected with TCR obtained from either high-or low-dose-responding T cell clones, suggesting that the affinity of TCRs for their ligands is not primary determinant of T cell antigen reactivity. The proliferative responses of all T cell clones to both peptide stimulation and to TCRb crosslinking revealed parallel dose-response curves. These results suggest that the TCR signal strength of effector T cells and threshold of antigen reactivity is determined by an intrinsic property, such as the TCR signalosome and/or intracellular signaling machinery. Finally, the antigen responses of high-and low-peptide-responding T cell clones reveal that clonal expansion and cytokine production of effector T cells occur independently of antigen concentration. Based on these results, the mechanisms underlying selection of high ''avidity" effector and memory T cells in response to pathogen are discussed.