The Mediator of Cellular Immunity

Abstract

Bacterial parasites that can survive and multiply intracellularly are notable for their ability to induce delayed-type hypersensitivity and a concomitant state of resistance that is expressed in the enhanced capacity of macrophages to kill ingested organisms (1). The mechanism by which macrophages become activated in this respect has not been determined, but the process clearly involves an activity of specifically sensitized lymphocytes. These are formed in the infected animal and can be detected by their ability to protect recipients against the homologous parasite.Cells that can protect normal rats against a challenge infection with Listeria monocylogenes (2) or Mycobacterium tuberculosis (Lefford, McGregor, and Mackaness, unpublished data) are delivered to the thoracic duct of donors infected with these organisms. The appearance of protective cells in the 15mph of Lisleria-infected subjects coincides with the influx of many newly formed lymphocytes: large, medium, and small (2). If the protective cells belong to a rapidly proliferating cell population, as the foregoing observation suggests, they should be vulnerable to agents that inhibit cell replication. Support for this notion was obtained in the current investigation in which the plant alkaloid vinblastine sulfate (Vbl) ~ was used to analyze the part played by dividing and nondividing lymphocytes in the transfer of cellular resistance to infection.It will be shown that a single injection of Vbl given to rats at the peak of their response to a primary infection with L. monocytogenes deletes specifically sensitized effector cells from the thoracic duct and from an inflammatory exudate induced in the peritoneal cavity. The results point to dividing (large) lymphocytes as the specific mediators of host resistance to L. monocytogenes and provide a plausible explanation for their rapid turnover and short circulating life-span (2).

CELLULAR MEDIATORS OF ANTI-LISTERIA IMMUNITY AS AN ENLARGED POPULATION OF SHORT-LIVED, REPLICATING T CELLS

“…This agrees with published findings on the vinblastine sensitivity of the mediators of anti-Listeria immunity in the rat (12). The conclusion that they are rapidly dividing cells is reinforced by the additional finding that an increase in their numbers in the spleen is associated with a major increase in DNA synthesis.…”

The Mediator of Cellular Immunity

“…Since small lymphocytes generated in the "rest" interval after the last injection of [3H]thymidine would not be expected to be labeled, it could be argued that newly formed small lymphocytes or possibly a subset of "short-lived" cells have an exudate-seeking capacity similar to that demonstrated for immunoblasts. This possibility cannot be discounted; for when rats with induced peritoneal exudates are transfused with TDL obtained from donors given a course of [3H]thymidine injections immediately before incannulation, labeled small lymphocytes, in addition to immunoblasts, are found later in the exudates (2). While some of these labeled small lymphocytes may have derived from exudate-seeking immunoblasts that escaped the inhibiting influence of vinblastine, others may have emigrated from the blood in a fully differentiated condition.…”

“…Studies using autoradiographic techniques have shown that after intravenous injection, labeled immunoblasts from the thoracic duct lymph of donor rats accumulate in substantial numbers in peritoneal exudates induced by killed bacteria (2,8). The exudate-seeking cells give rise by cell division and cell differentiation to a population of more lightly labeled small lymphocytes.…”

“…(Received for publication 11 February 1974) Earlier reports in this series (1,2) focused upon the cytokinetics and properties of the specifically sensitized lymphocytes which collaborate with macrophages in host resistance to Listeria monocytogenes. Evidence was obtained that the sensitized lymphocytes are generated in animals primarily immunized with the living organism.…”

“…The exudate-seeking cells give rise by cell division and cell differentiation to a population of more lightly labeled small lymphocytes. Since immunoblasts have a rapid turnover while small lymphocytes do not (7), these two cell types differ in their susceptibility to inhibition by drugs such as vinblastine (2) that are selectively toxic for dividing cells. Vinblastine was therefore used in experiments designed to measure the contributions made by immunoblasts and small lymphocytes to protective cell populations obtained from the inflamed peritoneal cavity of Listeria-infected rats.…”