Differences between T helper cell type I (T_h1) and T_h2 cell lines in signalling pathways for induction of contact‐dependent T cell help

Abstract

B cells get help in the antibody response by presenting antigen to helper T (Th) cells. Upon antigen recognition, T cells produce lymphokines that act as growth and differentiation factors for B cells, but resting B cells require additional helper signals that depend on cell contact with an activated Th cell. Like lymphokine secretion, contact help must be induced by antigen recognition or antigen receptor cross-linking in continuous Th cell lines. In the mouse, most CD4+ T cell lines can be classified into one of two stable differentiation states, Th1 or Th2, which produce different lymphokines and have different effector functions, activation requirements and cytoplasmic signalling mechanisms. This report demonstrates additional differences between Th1 and Th2 cell lines in the signalling pathways leading from the T cell antigen receptor to the induction of Th functions. In a system dependent on antigen presentation by B cells, B cell proliferation driven by Th2 cells but not Th1 cells was blocked by acute treatment with phorbol esters. Further experiments showed that phorbol esters blocked the induction of both contact help and lymphokine production in Th2 cells but not in Th1 cells. However, depletion of protein kinase C (PKC) activity by prolonged treatment of T cells with high concentrations of phorbol esters blocked induction of contact help and lymphokine production in Th1 cells but not in Th2 cells. These findings support the hypothesis that Th2 cells use a signalling pathway that is independent of PKC and that PKC activation can block this pathway. Since contact help and lymphokine secretion are affected in parallel, this difference between Th1 and Th2 cells probably reflects early events in the signalling pathway. Contact help and lymphokine production could be dissociated with cholera toxin and other cAMP agonists, but this dissociation could be explained by non-cAMP-related effects of cholera toxin on induction of contact help in Th2 cells, and by the direct effect of cAMP agonists on interleukin 2 gene transcription in Th1 cells reported by other laboratories.

Antigen and helper T lymphocytes activate B lymphocytes by distinct signaling pathways

“…Our recently published experiments show that induction of ITCH is strikingly different between Thl and Th2 cells in sensitivity to phorbol esters, PKC depletion and cholera toxin [9]. However, once ITCH is induced, delivery of …”

“…To make sure that PKC was actually depleted by this treatment, phosphatidylserine-and diacylglycerol-dependent kinase activity in the subcellular fractions of the B cells was measured as described [27] with some modifications [9], except that the ATP concentration was increased from 5 to 50 p ,~. PKC activity was calculated using the following formula: cpm in the presence of calcium ion, phosphatidylserine, and diolein minus cpm in the presence of calcium ion only.…”

Breakage of B Cell Tolerance and Autoantibody Production in Anti-erythrocyte Transgenic Mice

“…In contrast to abrogation of sIgmediated apoptosis of B cells, Th-derived cytokines act on B cells more efficiently than membrane molecules on Th cells. Although B cells are activated and start DNA synthesis through fixed T cells alone [27] or membranes from activated T cells alone [28], these responses are greatly enhanced by the addition of exogenous cytokines [29]. The cytokines involved in the differentiation of B cells into APCs are Th2 cell-derived 1L-4 or IL-5.…”

Analysis of transmembrane signalling and T cell defects associated with idiopathic thrombocytopenic purpura (ITP)

“…T cell signalling leading to the production of Th 1 vs Th 2 cytokines has been shown by a number of investigators to be different (21,(25)(26)(27)(28). T cell signalling leading to Th 1 cytokine secretion has been most extensively studied in relation to production of IL-2.…”

“…Transmembrane signalling leading to IL-4 production in the Th 2 cell subset has been somewhat less well worked out, but it appears that IL-4 production utilizes a different signalling pathway than production of IL-2 (21,(25)(26)(27)(28). In addition, it has been shown previously that defective T cell transmembrane signalling along the PKC-p21 ras -MAPK cascade can severely affect TCR-dependent IL-4 production, without any effect on IL-2 production (15)(16)(17).…”