The intensity of T cell receptor engagement determines the cytokine pattern of human allergen‐specific T helper cells

Abstract

Enhanced production of T helper (Th)2 cytokines by allergen-specific Th cells plays a major role in the induction and maintenance of IgE-mediated allergic disorders. The mechanism that triggers this type of response in atopic individuals is not fully understood. Allergen-specific human Th cell clones produce interleukin (IL)-4 and low or undetectable levels of interferon (IFN)-gamma after stimulation with low concentrations of antigen. However, these Th cell clones are capable of generating significant amounts of IFN-gamma after optimal activation through their T cell receptor (TcR). Allergen-specific Th cell clones isolated from allergic individuals required higher doses of antigen to reach the plateau of proliferation and to generate Th0 cytokine responses than their counterparts isolated from nonallergic subjects. On the other hand, if allergen was replaced by anti-CD3 monoclonal antibody (mAb), both allergic and nonallergic Th cell clones attained the highest level of proliferation and significant IFN-gamma production in response to equivalent concentrations of anti-CD3 mAb. These results indicate that the strength of T cell ligation, which can be modulated by the availability of the TcR ligand, controls the balance of Thl/Th2 cytokines produced by memory Th cells in vitro. In the particular case of bee venom phospholipase A2, it is shown that the expression of allergen-specific surface Ig on antigen-presenting B cells has little influence on antigen uptake and therefore in determining the levels of T cell activation and cytokine production. Alternatively, the affinity of particular major histocompatibility complex class II molecules on antigen-presenting cells for allergen-derived peptides might determine the amount of specific ligand presented to the Th cells and play a decisive role skewing the Th cell cytokine production towards Th1 or Th2 phenotypes. These findings, which are consistent with the changes in cytokine patterns observed following clinical hyposensitization, suggest that polarized human Th2 cell subsets still retain the capacity to modulate their cytokine pattern.

Threshold Signaling of Human Th0 Cells in Activation and Anergy: Modulation of Effector Function by Altered TCR Ligand

“…These T cells clones were selected for this study because they all recognize the same T cell epitope in Der p 2 (residues 28 -40) in association with the HLA class II molecule DRB1*1101. Although variation was observed in the pattern of response elicited by individual T cell clones following recognition of the analogue peptide (p 2, 28 -40A 34,36 ), the overlying trend was for a shift in effector function from the Th2 to Th1 pathway. Stimulation of AC1.1, AC34.11, and AC34.26 cells with p 2, 28 -40A 34,36 enhanced IFN-␥ secretion as compared with the native peptide at equimolar concentrations, whereas proliferation and IL-5 production induced by either peptide were similar in magnitude (Table I).…”

“…The Der p 2 peptides, p 2, 28 -40 (IIHRGKPFQLEAV) and p 2, 28 -40A 34,36 (IIHRGKAFALEAV) were purchased from Genosys (Cambridge, U.K.). The peptides were tested for nonspecific immunosuppressive and mitogenic activity on cloned T cells reactive with influenza virus hemagglutinin.…”

“…Thus, the biological activity displayed by the analogue peptide is not the result of a contaminant. Biotinylated peptides p 2, 28 -40 and p 2, 28 -40A 34,36 were purchased from Advanced Biotechnology Centre (Imperial College School of Medicine at Charing Cross Hospital, London, U.K.).…”

“…Binding affinity of peptides p 2, 28 -40 and its analogue p 2, 28 -40A 34,36 to HLA-DRB1*1101 was determined as follows: biotinylated versions of both peptides were incubated with live L-1101 cells (3 ϫ 10 5 cells/well of a 96-well round-bottom tissue culture plate), over a range of concentrations, in a total volume of 200 l RPMI 1640/1% FCS for 4 h. Cells were washed and incubated with 10 g/ml avidin D FITC (Vector Laboratories, Peterborough, U.K.) for 30 min at 4°C and washed. Dead cells were excluded from the analysis by staining with 10 g/ml propidium iodide.…”

T‐cell tolerance in allergic response

“…1). However, T-cell unresponsiveness (anergy) can also be induced in vitro, when pure antigen-specific T cells are incubated with peptides in the absence of antigen presenting cells (APCs) (25). Under these conditions, T cells are possibly presenting the antigens themselves, but fail to costimulate each other and therefore, receive only one T-cell activation signal.…”