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Characterization of Cells That Suppress the Cytotoxic Activity of T Lymphocytes

I. Quantitative Measurement of Inhibitor Cells¹

From the Department of Medical Biophysics and the Institute of Medical Sciences, University of Toronto and the Ontario Cancer Institute, 500 Sherbourne St., Toronto, Ontario, Canada M4X 1K9

Abstract

Target cell lysis by sensitized cytolytic T lymphocytes (CTL) may be conveniently quantitated by ⁵¹Cr release. By fitting to the formula, P (% specific release) = 100 (1-e^{-N t}), one obtains , the relative frequency of CTL in N lymphoid cells. Using a microassay and murine sarcoma target cells, we observed an unexpected decrease in lysis whenever effectors obtained from a graft-vs-host reaction were tested at high concentrations. This inhibition was not observed with CTL generated by an MLC reaction. Inhibition could not be explained by nonspecific mechanical ‘crowding’, reutilization of released isotope, suppression of released from dead target cells, or the particular strain combination and target used. By modifying the formula to allow suppression of CTL by a stochastic cell-cell interaction with a suppressor cell, we found that P = 100 (1-e^{-N ate- N}) adequately fitted the data, where N is proportional to inhibitor content. An 18- to 24-hr incubation at 37°C but not 4°C allowed selective depletion or enrichment of inhibitors; in mixing experiments, both parameters Nt and N behaved stoichiometrically as independent cellular properties. The inhibitor was resistant to concentrations of anti-T cell (RAMB) serum + complement which killed CTL. A similar inhibitor arose in vivo during an anti-tumour allograft response. The ability to quantitate CTL and inhibitor activities from titration curves provides a technique for studying the identity and mechanism of suppressor cells acting at the effector stage of cell-mediated immunity.

Footnotes

¹ This work was supported by the Medical Research Council of Canada (MT-3017) and the National Cancer Institute of Canada.

² David Clark was supported by a Fellowship from the Medical Research Council.

³ Send correspondence to: Dr. R. G. Miller, Ontario Cancer Institute, 500 Sherbourne Street, Toronto, Ontario, Canada M4X 1K9.

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