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Mechanisms whereby Lytic Granules from Cytotoxic T Lymphocytes Damage Guinea Pig Ventricular Myocytes
Author(s) -
BINAH O.,
KLINE R.,
BERKE G.,
HOFFMAN B.
Publication year - 1993
Publication title -
scandinavian journal of immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.934
H-Index - 88
eISSN - 1365-3083
pISSN - 0300-9475
DOI - 10.1111/j.1365-3083.1993.tb01664.x
Subject(s) - myocyte , patch clamp , membrane potential , biophysics , clamp , chemistry , reversal potential , guinea pig , resting potential , cardiology , medicine , electrophysiology , biology , mechanical engineering , clamping , engineering
During immunological rejection of the transplanted heart, cytoloxic T lymphocytes (CTL) infiltrate the myocardium and by damaging the myocytes contribute to loss of function. To address one important aspect of heart transplant rejection, we investigated in guinea pig ventricular myocytes how CTL‐derived lytic granules containing the pore‐forming protein perform reduce the membrane potential ( V m) and cause cell damage. The reduction in V M was biphasic; within 8.4 × 1.9 min V M was reduced from a control value of ‐78.4 × 1.9 mV to ‐69.9 × 3.5 mV. Subsequently, within 6.7 × 2.1 min V M declined to ‐ 3.4 × 1.2 mV. associated with a progressive contracture. Under whole cell voltage clamp, in myocytes held at their resting potential (V M = ‐76.2 × 0.9 mV), granules induced discrete inward current steps (resembling “single channel’activity), with a mean amplitude of ‐ 86.8 × 1.4 pA and open times lasting from seconds up to several minutes. The mean conductance and reversal potential calculated from the linear regression analysis of the I‐V relations were 1390 pS and ‐ 6.8 mV. respectively. The probable non‐selectivity of these “channels” and the resultant loss of membrane K + selectivity can account for the reduction in V M . At the same time, opening of these pores leads to Ca‐ + overload, resulting in contracture and cell damage.