Alternatively activated macrophages actively inhibit proliferation of peripheral blood lymphocytes and CD4⁺ T cells in vitro

Abstract

SUMMARYWe compared the immunological functions of interferon-c (IFN-c)-induced, classically activated macrophages (caMW) and of interleukin-4 (IL-4)-and glucocorticoid-induced, alternatively activated macrophages (aaMW) in a human co-culture system in vitro. Proliferation of peripheral blood leucocytes (PBL) or CD4+ T cells mediated by optimal doses of phytohaemagglutinin (PHA) or concanavalin A (Con A) was only marginally influenced by caMW, but was strongly inhibited by aaMW. The degree of lymphocyte proliferation sustained in the presence of caMW was gradually reduced in a dose-dependent fashion by the addition of aaMW. Flow cytometric analysis revealed that expression of costimulatory molecules such as CD11a, CD40, CD54, CD58, CD80 and CD86 did not vary significantly between caMW and aaMW and was low for CD58, CD80 and CD86. As shown by reverse transcriptase-polymerase chain reaction (RT-PCR) analysis, IL-10 was expressed in caMW, aaMW and control macrophages; the level of expression of IL-10 was slightly enhanced in aaMW. Neither neutralizing anti-IL-10 antibodies, indomethacin nor NG-monomethyl--arginine (NMMLA) was able to reverse aaMW-mediated inhibition of lymphocyte proliferation. Of several agents interfering with various second messenger pathways, cAMP and the Ca2+-ionophor A23187 inhibited differentiation of cultured human monocytes into phenotypically mature aaMW expressing MS-1 high molecular weight protein (MS-1-HMWP) and RM 3/1 antigen, and prevented the suppressive action of aaMW on lymphocyte proliferation. In conclusion, these results show that aaMW actively inhibit mitogen-mediated proliferation of PBL and CD4+ T cells independently of the expression of costimulatory molecules and of IL-10, NO or prostaglandin synthesis, and that inhibition of phenotypic differentiation of aaMW is paralleled by a lack of functional maturation. Thus, fully matured aaMW may be functional in down-regulating CD4+ T-cell-mediated immune reactions by an as yet unknown mechanism.

Nitric Oxide-Independent CTL Suppression during Tumor Progression: Association with Arginase-Producing (M2) Myeloid Cells

“…M2 cells are considered to induce Th2 differentiation of CD4 ϩ T cells and cause Th1 tolerance (38,51,69). They may have potential roles in immune suppression (34,62). Loke et al (34) reported that the IL-4-induced alternatively activated macrophages reversibly inhibited T cell proliferation by a cell-to-cell contact mechanism, similar to the suppression we observed in tumor progressors.…”

Immortalized Myeloid Suppressor Cells Trigger Apoptosis in Antigen-Activated T Lymphocytes

“…Functionally, they can induce tolerance and down-regulate inflammatory responses (28). In one report, IL-4-stimulated human macrophages inhibited mitogen-mediated proliferation of CD4 ϩ lymphocytes by an as yet unknown mechanism (29). Our experiments suggest a relationship between our myeloid suppressors and the alternatively activated macrophages, particularly in the case of MSC-2, which not only gains the suppressive phenotype in response to IL-4 (Figs.…”

Modeling the immune rheostat of macrophages in the lung in response to infection

“…I g is produced by T cells upon cue from I 12 and MHC displayed on the membrane of C. A inhibits production of I g by T cells (7). Including an I g decay term gives the following:…”

“…Martinez and colleagues also refer to these as M1 macrophages, characterizing them as having elevated expression of MHC-II, CD80, and CD86 costimulatory molecules and promoting TH1 differentiation and IFN-␥ production by T cells via the production of IL-12 (4). A different, more recently studied class of macrophages, is known as alternatively activated macrophages (AAM) (2,(5)(6)(7)(8). Also referred to as M2a macrophages, these macrophages have a phenotype resembling macrophages activated by Interleukin-4 (IL-4) or IL-13 and are characterized by the up-regulation of scavenger receptors and the mannose receptor.…”