TITLE:
Activating interactions of sulfanilamides with T cell receptors
AUTHORS:
Stephan Watkins, Werner J. Pichler
KEYWORDS:
p-i Concept; Drug Hypersensitivity; Sulfamethoxazole; TCR Signaling; TCR Specificity; TCR-Modelling; T Cell Clones
JOURNAL NAME:
Open Journal of Immunology,
Vol.3 No.3,
September
20,
2013
ABSTRACT: Activation and expansion of drug reactive T cells are key
features in drug hypersensitivity reactions. Drugs may interact directly with immune
receptors such as the human leukocyte antigens (HLA) or the T-cell receptors
(TCR) itself, the pharmacological interaction [p-i] concept. To analyze whether
the drug sulfamethoxazole (SMX) interacts directly
with the TCR and thereby contributing to signaling and T cell activation, we
analyze two SMX specific T cell clones (TCC “1.3”and “H13”).
Proliferation to SMX and 11 related sulfanilamides, Ca++ influx in drug
stimulated T-cells and the inhibitory effect of non-reactive sulfanilamides on
SMX stimulation were analyzed. In silico docking of SMX and related sulfanilamide to the TCR were used to identify
possible drug binding sites, and correlated to in vitro data to find the correct docking. In Ca++ influx assays,
reactions occurred as early as 14 sec after adding SMX to TCC and APC. The
broadly reactive clone (“H13”)
was stimulated by 5 additional sulfanilamide, while one TCC (“1.3”) was reactive exclusively with SMX
but not other sulfanilamides. Competition experiments with sulfanilamide
inhibited SMX induced Ca++ influx and proliferation of the TCC1.3 ina dose dependent way. Docking experiments
with SMX and related sulfanilamides confirmed and explained the in vitro data as docking localized
binding sites for SMX and the 5 stimulating sulfanilamides on the CDR2β domain of the clone H13, while the 6
non-stimulatory SA failed to bind. In TCC 1.3, SMX could be docked on the CDR3α
of the TCR. The other, non-stimulatory but inhibitory SA could also be docked
to the same site. The combined analysis of in
vitro and in silico data show
that sulfanilamide can bind directly to TCRs. It shows that TCR, like other
receptors, appear to be reamenable to manipulations by small molecules.