Tumor modulation of autoreactivity: decreased macrophage and autoreactive T cell interactions.
The autologous mixed lymphocyte reaction (AMLR) is an in vitro measure of autoreactivity, a key mechanism in immune homeostasis. In this system, macrophages (M phi) act as accessory cells to autoreactive L3T4+ T cells by presenting self-Ia and releasing soluble modulators. During tumor growth, changes occur in M phi and T cells. Tumor-bearing host (TBH) M phi have a reduced ability to act as accessory cells. In fact, TBH M phi suppressed autoreactivity by 60-70%. The decrease in TBH M phi or T-cell abilities was not due to differences in cell numbers or incubation time. Because tumor growth causes increased prostaglandin E2 (PGE2) production by M phi, indomethacin was used to assess the contribution of prostaglandins. Normal and TBH T-cell reactivity increased nearly 50% when stimulated by normal host M phi, while normal and TBH T-cell reactivity increased nearly 100% when stimulated by TBH M phi. Thus increased prostaglandin production is partly responsible for the increased TBH suppressor M phi activity and in the normal host, suppressor M phi may be responsible for maintaining immune regulation. To assess the direct role of prostaglandins in T-cell hyporesponsiveness, PGE2 was titrated into the cultures. PGE2 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 PGE2 (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 (TH)-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 M phi-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 M phi) only returned to normal host unstimulated levels. Tumor growth modulates the immune response at least by (i) decreasing the accessory cell abilities of TBH M phi through decreased Ia expression and increased production of suppressive molecules such as prostaglandins; and (ii) decreasing the responsiveness to immune enhancing factors by TH cells.
Yurochko
A D
AD
Department of Biology, Microbiology, Virginia Polytechnic Institute and State University, Blacksburg 24061-0406.
Burger
C J
CJ
Elgert
K D
KD
D000818:Animals; D015551:Autoimmunity / Q000276:immunology / Q000502:physiology*; D002450:Cell Communication / Q000187:drug effects / Q000502:physiology; D002452:Cell Count / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D005354:Fibrosarcoma / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D007111:Immunity, Cellular / Q000187:drug effects / Q000276:immunology; D007165:Immunosuppression Therapy; D007375:Interleukin-1 / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D008264:Macrophages / Q000378:metabolism / Q000502:physiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011453:Prostaglandins / Q000378:metabolism / Q000502:physiology; D013491:Suppressor Factors, Immunologic / Q000378:metabolism / Q000502:physiology; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000502:physiology
D007375:Interleukin-1; D007376:Interleukin-2; D011453:Prostaglandins; D013491:Suppressor Factors, Immunologic; D015847:Interleukin-4