Tumor modulation of autoreactivity: Decreased macrophage and autoreactive T cell interactions

• Published in: Cellular immunology Vol. 127; no. 1; pp. 105 - 119
• Main Authors: Yurochko, Andrew D., Burger, Carol J., Elgert, Klaus D.
• Format: Journal Article
• Language: English
• Published: San Diego, CA Elsevier Inc 15.04.1990; Elsevier
• Subjects: Animals; Autoimmunity - immunology; Autoimmunity - physiology; Biological and medical sciences; Cell Communication - drug effects; Cell Communication - physiology; Cell Count - drug effects; Cell Division - drug effects; Fibrosarcoma - immunology; Fibrosarcoma - pathology; Fibrosarcoma - physiopathology; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Immunity, Cellular - drug effects; Immunity, Cellular - immunology; Immunobiology; Immunosuppression; Interleukin-1 - pharmacology; Interleukin-2 - pharmacology; Interleukin-4 - pharmacology; Lymphocyte Activation - drug effects; Macrophages - metabolism; Macrophages - physiology; Male; Mice; Mice, Inbred BALB C; Modulation of the immune response (stimulation, suppression); Prostaglandins - metabolism; Prostaglandins - physiology; Suppressor Factors, Immunologic - metabolism; Suppressor Factors, Immunologic - physiology; T-Lymphocytes - drug effects; T-Lymphocytes - metabolism; T-Lymphocytes - physiology; T-Lymphocytes, Helper-Inducer - drug effects; T-Lymphocytes, Helper-Inducer - physiology; Antigen presentation; Mixed lymphocyte reaction; Immune response; Arachidonic acid derivatives; Interleukin; Rodentia; Cytokine; Prostaglandin E2; Accessory cell; Helper cell; Biosynthesis; Autologous system; Cell subpopulation; Dose activity relation; Vertebrata; Immunosuppression; Mammalia; Mouse; Modulation; T-Lymphocyte; Tumor; Macrophage
• ISSN: 0008-8749; 1090-2163
• DOI: 10.1016/0008-8749(90)90118-B

The autologous mixed lymphocyte reaction (AMLR) is an in vitro measure of autoreactivity, a key mechanism in immune homeostasis. In this system, macrophages (Mφ) act as accessory cells to autoreactive L3T4 + T cells by presenting self-Ia and releasing soluble modulators. During tumor growth, changes occur in Mφ and T cells. Tumor-bearing host (TBH) Mφ have a reduced ability to act as accessory cells. In fact, TBH Mφ suppressed autoreactivity by 60–70%. The decrease in TBH Mφ or T-cell abilities was not due to differences in cell numbers or incubation time. Because tumor growth causes increased prostaglandin E 2 (PGE 2) production by Mφ, indomethacin was used to assess the contribution of prostaglandins. Normal and TBH T-cell reactivity increased nearly 50% when stimulated by normal host Mφ, while normal and TBH T-cell reactivity increased nearly 100% when stimulated by TBH Mφ. Thus increased prostaglandin production is partly responsible for the increased TBH suppressor Mφ activity and in the normal host, suppressor Mφ may be responsible for maintaining immune regulation. To assess the direct role of prostaglandins in T-cell hyporesponsiveness, PGE 2 was titrated into the cultures. PGE 2 suppressed normal and TBH T-cell responsiveness in a dose-dependent manner. Normal host T cells were suppressed to a greater extent than TBH T cells by PGE 2 (66% versus 42% suppression, respectively). Reduced Ia expression and active suppressor mechanisms are not the only mechanisms mediating hypoautoreactivity during tumor growth. TBH autoreactive L3T4 + T cells were less responsive to self-Ia; they were only 60–80% as reactive as their normal counterparts. To address whether the helper T (T H)-cell defect involved cytokines, T cells were treated with interleukin (IL)-1, IL-2, and IL-4. In all cases, the TBH T-cell response to the factors was decreased (only 60–75% as reactive as normal T cells). Because TBH Mφ-mediated suppression can override the addition of IL-1, IL-2, and IL-4, indomethacin was also added with the exogenous interleukins. This coaddition significantly enhanced normal host autoreactivity above control levels while TBH autoreactivity (the combination of TBH T cells and TBH Mφ) only returned to normal host unstimulated levels. Tumor growth modulates the immune response at least by (i) decreasing the accessory cell abilities of TBH Mφ through decreased Ia expression and increased production of suppressive molecules such as prostaglandins; and (ii) decreasing the responsiveness to immune enhancing factors by T H cells.