Macrophage activation: dissociation of cytotoxic activity from Ia-A antigen expression.

Abstract

Peritoneal macrophages were obtained from DBA/2 mice that were untreated or after the injection of bacillus Cainette-Guerin (BCG), thioglycollate broth, proteose-peptone broth, or gamma-irradiated P-815 tumor cells. These macrophages were "activated" to become cytotoxic for a fibroblast cell line (L 929) by the addition of lymphokines (LKs), lipopolysaccharide (LPS), or fibroblast interferon , and the expression of I region-associated antigens (Ia-Ad) on the macrophages was examined both before and after activation. Thioglycollateelicited macrophages became Ia-A' when activated by LKs, but they remained la-A-when activated by LPS or IFN-f3. Resident macrophages and proteose-peptone-elicited macrophages remained Ia-A-when activated with LKs. Macrophages from BCGinfected mice were both Ia-A' and cytotoxic for tumor cells without further treatment. In contrast, macrophages from mice injected with gamma-irradiated P-815 mastocytoma cells were Ia-A+ but not cytotoxic, and these macrophages could not be made cytotoxic by incubation with LKs. The cultured macrophage-like cell lines P388D1 and WEHI-3 became Ia-A+ after incubation with LKs, and this treatment amplified the cytotoxicity of both cell lines. We conclude that a number of factors are important in determining whether Ia-A expression accompanies macrophage activation and that Ia-A is irrelevant as a surface marker for macrophage activation.I region-associated antigens (la) have been detected on distinct subpopulations of macrophages. Most macrophages from the spleen, thymus, and liver are la', whereas la-macrophages predominate in the peritoneal cavity (1-3). It has been shown that only the Ia+ subset of macrophages is effective in presenting antigen to T cells (4, 5). In addition, Ia expression appears to be a prerequisite for macrophages to act as accessory cells for lymphokine (LK) production and lymphocyte proliferation (6, 7).Recently, it has been demonstrated that LK preparations can induce la-macrophages to become Ia+ in vitro (8-10). Similar preparations of LKs are known to contain macrophage-activating factor (MAF) which stimulates macrophages to become cytotoxic for tumor cells (11). This raises the questions of whether the Ia' macrophage is the cytotoxic macrophage and whether La antigens can be used as a surface marker for macrophage activation.In this report, we present evidence indicating that the cytotoxic macrophage can be either Ia-A+ or Ia-A-, depending upon the procedures used for elicitation and activation of it. Also, Ia-A was found not to be a useful marker for macrophage activation because Ia-A expression was neither necessary nor sufficient for macrophage cytotoxicity. MATERIALS AND METHODSMice. Our source of peritoneal macrophages was DBA/2 mice that were less than 3 months old (The Jackson Laboratory).Elicitation of Peritoneal Macrophages. Peritoneal exudate cells were collected by lavage with 5 ml of sterile Eagle minimal essential medium. Resident cells were removed from untreated mice. Cells were also obtained (a) 3-4 days ...

Modulation of Major Histocompatibility Complex (MHC) Expression by Interferons and Microbial Agents

“…Table II showing that MHC class II expression is rather low in resting BMM0 but is markedly amplified upon interaction with MAF and IFN-y are in keeping with various earlier works [20,28,33], It is noteworthy that the ability of BMM(^ to enhance MHC class II expression is already fully developed shortly after their adherence to the substratum on days 5-7 after initation of the culture, i,e, at a fairly early stage of their maturation and with virtually all BMM<^ becoming MHC class Il-positive (Table II), Since the marked increase in MHC class II expression by IFN-y was detected with each of the five monoclonal antibodies which at least to some extent recognize different antigenic structures on the MHC class II molecule, it appears likely that IFN-y increases expression of various if not all MHC class II antigens. These findings in rats are in keeping with observations in humans, showing that all monocytes have the potential to express high levels of all three classes of MHC class II molecules [5,10],…”

Infection of DBA/2 or C3H/HeJ mice by intraperitoneal injection of vaccinia virus elicits activated macrophages, cytolytic and cytostatic for S91-melanoma tumor cells

“…It was proposed that a single lymphokine, gamma-interferon, could mediate both the activation of macrophages and stimulate the expression of Ia antigen [34,43,51]. In culture these activities or capacities could be dissociated; the expression of Ia antigen was found to be neither necessary nor sufficient for macrophage cytotoxicity [9]. The results of the in vitro experiments reported here (Table 4) provide further support for this conclusion.…”

Antigen-Presenting Function of the Macrophage

“…The relationship between the two in vivo has not been fully explained. Certainly, la-positive macrophages in tissues did not exhibit cytotoxicity (132). However, the la-positive macrophages in strong or continuous cellular immune reactions, which are strongly la-positive, may exercise both functions (132).…”