Mechanisms of Trypanosoma cruzi-induced down-regulation of lymphocyte function. Inhibition of transcription and expression of IL-2 receptor gamma (p64IL-2R) and beta (p70IL-2R) chain molecules in activated normal human lymphocytes.
Acute infection with Trypanosoma cruzi, the agent of Chagas' disease, is accompanied by multiple manifestations of immunosuppression, and this parasite has been shown to inhibit T and B lymphocyte functions in vitro through a mechanism involving impaired membrane expression of at least the p55IL-2R (IL-2R alpha) and p70IL-2R (IL-2R beta) components of the multimeric high affinity IL-2R complex. We document in this paper that addition of T. cruzi or a parasite-conditioned medium (trypanosomal immunosuppressive factor (TIF) to cultures of PHA-stimulated normal human blood lymphocytes markedly decreases the cytoplasmic levels of p64IL-2R and p70IL-2R molecules, i.e., the two IL-2R chains that bind IL-2 and participate in signal transduction. These effects highlighted the ability of T. cruzi to curtail biosynthesis of these IL-2R chains and weakened the possibility that decreased membrane IL-2R expression results exclusively from altered chain transportation to the lymphocyte surface. Additional support for impaired lymphocyte production of IL-2R components was derived from northern blot analyses demonstrating TIF-induced decreases in p64IL-2R and p70IL-2R mRNA levels. These reductions are unlikely to be due to conditions affecting mRNA stability, since the rates of decay of both mRNA species were nearly identical in the presence and in the absence of TIF. In addition, nuclear run-on studies revealed that transcription of the p64IL-2R, p70IL-2R, and p55IL-2R genes, but not that of the CD69 gene, was below normal levels in PHA-stimulated lymphocytes incubated with TIF. These results suggest that altered gene transcription is involved in the mechanism by which T. cruzi down-regulates the expression of all the known components of the high affinity IL-2R.
Majumder
S
S
Department of Microbiology, Michigan State University, East Lansing 48824, USA.
Kierszenbaum
F
F
D000818:Animals; D015536:Down-Regulation / Q000276:immunology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000235:genetics*; D008214:Lymphocytes / Q000276:immunology* / Q000378:metabolism; D010835:Phytohemagglutinins / Q000494:pharmacology; D015375:Receptors, Interleukin-2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics*; D014158:Transcription, Genetic / Q000276:immunology*; D014349:Trypanosoma cruzi / Q000737:chemistry / Q000276:immunology*
D007166:Immunosuppressive Agents; D010835:Phytohemagglutinins; D015375:Receptors, Interleukin-2