Phenotypic and functional characterization of splenic macrophages associated with progression of the D1-DMBA-3 mammary adenocarcinoma

Date of Award




Degree Name

Doctor of Philosophy (Ph.D.)


Microbiology and Immunology

First Committee Member

Diana M. Lopez - Committee Chair


Tumor burden has been shown to induce a variety of phenotypic and functional changes in the cellular constituents of the host's immune system. These changes have been implicated as one way in which the tumor regulates the host immune response, thereby avoiding rejection. Alterations in resident splenocytes from D1-DMBA-3 mammary adenocarcinoma bearing Balb/cCrgl mice were noted on routine histologic specimens. A five-fold increase in macrophage-like cells was observed and these cells were phenotypically and functionally analyzed to establish their role in tumor induced alterations of the host immune response. mAb staining determined that these cells were Mac-1$\sp{+}$, -2$\sp{+}$ and I-A/E$\sp{\rm d+}$, a phenotype not found in normal splenic M$\emptyset$ subpopulations. The TB M$\emptyset$'s were found to mediate down-regulation of both polyclonal and antigen specific T and B cell responses in vitro and in vivo. B cell responses were suppressed via TB M$\emptyset$ PGE$\sb2$ production. T cell responses were relatively refractory to PGE$\sb2$ mediated down-regulation. They were suppressed by a contact-dependent T cell - M$\emptyset$ interaction. This TB M$\emptyset$ down-regulatory mechanism was found to act at a stage late in the T cell activation cascade, after IL-2 production, affecting, instead, IL-2 utilization. Finally, with respect to antigen relevant to the D1-DMBA-3 tumor system, TB-M$\emptyset$ significantly suppressed normal proliferative response and CTL generation to a TAA preparation. Further, those cells that were generated acted as TAA-specific T suppressor cells. It was found that unlike normal Mac-1$\sp{+}$, -2$\sp{-}$ M$\emptyset$, which presented TAA in the context of I-A$\sp{\rm d}$, Mac-1$\sp{+}$, -2$\sp{+}$ TB M$\emptyset$ TAA presentation was in the context of I-E$\sp{\rm d}$. This was confirmed by limiting dilution analysis of TAA specific T cells and suggests that TB Mac-1$\sp{+}$, -2$\sp{+}$ M$\emptyset$ may preferentially present TAA to antigen specific T suppressor cells or their inducers which are I-E$\sp{\rm d}$ restricted. TB M$\emptyset$, then, appear to mediate down-regulation of the host immune response in three distinct manners: (1) through PGE$\sb2$ production; (2) a TB M$\emptyset$ -T cell contact dependent, but non MHC-specific, mechanism; and (3) a TAA-specific alteration in restriction specificity of presentation, leading to generation of antigen specific T suppressor cells.


Health Sciences, Immunology

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