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Studies on the Mechanism of Lymphocyte-Mediated Cytolysis

III. The Role of Microfilaments and Microtubules¹

Department of Medicine of the Johns Hopkins University and the O'Neill Memorial Research Laboratories of the Good Samaritan Hospital, Baltimore, Maryland

Abstract

The effect of cytochalasin B and colchicine on thymus-derived lymphocyte-mediated cytolysis in vitro has been studied.

Cytochalasin B reversibly inhibited (range 0.1 µg/ml to 10 µg/ml) the cytolysis of DBA/2 mastocytoma cells by splenic lymphocytes from allo-immunized C57BL mice. The drug itself was not cytotoxic. No evidence was found that "activation" of lymphocytes occurred in the presence of target cells and cytochalasin B. Inhibition occurred at a very early stage in the cytolytic pathway, possibly by preventing intimate contact between target cell antigens and lymphocyte receptor sites.

Colchicine inhibited cytolysis irreversibly (range 10^-7 M to 10^-3 M). This inhibitor was found to act exclusively on the effector lymphocyte population, preventing, by a non-cytotoxic mechanism, the expression of cytolytic activity. Colchicine appeared to act later in the cytolytic cycle than cytochalasin B. Supportive evidence of this viewpoint was the finding that reaction mixtures inhibited with cytochalasin B were further suppressed when this drug was removed and replaced with colchicine.

Cytochalasin B and colchicine were neither additive nor synergistic in their combined inhibitory activity. The inhibition observed with mixtures of these drugs was always equivalent to that found with the more potent inhibitor alone.

Among other activities, cytochalasin B has been demonstrated to affect microfilaments. The reversibility with which cytochalasin B inhibits cytolysis and the dose range over which it is active are consistent with the view that its inhibitory activity in this system is microfilament associated. Colchicine shows a great specificity for binding to the dimeric sub-unit of microtubules, and by so doing prevents microtubular aggregation. The present study suggests that this binding is the basis for inhibition of cytolysis. Consequently, the present findings support a role for both microfilaments and microtubules in lymphocyte-mediated cytolysis; the former possibly being necessary for effective lymphocyte-target cell interactions, the latter apparently being involved in a terminal cellular secretory event associated with the lysis of the target cell.

Footnotes

¹ This is Communication 55 from the O'Neill Memorial Laboratories.

² Recipient of Research Career Development Award AI 42373 from the National Institutes of Allergy and Infectious Diseases.

³ Recipient of Research Career Development Award AI 70393 from the National Institutes of Allergy and Infectious Diseases.

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				T. B. Strom, M. R. Garovoy, C. B. Carpenter, and J. P. Merrill Microtubule Function in Immune and Nonimmune Lymphocyte-Mediated Cytotoxicity Science, July 13, 1973; 181(4095): 171 - 173. [Abstract] [PDF]