title: T-helper lymphocytes specific for myelin basic protein: activation-induced refractoriness of IL-2 production pathways augments an anti-CD4-mediated proliferative deficit.
abstract: Cloned and uncloned lines of encephalitogenic rat T cells produce IL-2 when activated with myelin basic protein (MBP) in the presence of irradiated splenocytes (SPL). Although these T cells use IL-2 as a primary mediator of autocrine growth, regulatory mechanisms controlling production of IL-2 have yet to be fully defined. This study shows that T cells reactivated within approximately 7 days of a prior activation were refractory to the reinduction of MBP-stimulated IL-2 production. In contrast, T cells rested for > 7 days regained the ability to produce optimal levels of IL-2 during activation with MBP. Cultures containing both activated and resting T cells responded to MBP by producing levels of IL-2 that were similar to those obtained from control cultures of resting T cells. The lack of IL-2 production during this refractory phase was associated with lowered responsiveness to MBP in proliferative assays as evidenced by right-shifted dose-response curves. However, this refractory phase did not affect the magnitude of responses elicited by optimal concentrations of MBP. The dissociation of proliferation from IL-2 production suggested parallel pathways of autocrine growth. Indeed, anti-MBP-proliferative responses were mediated by two distinct mechanisms distinguished by differential susceptibility to the anti-CD4 mAb W3/25. The W3/25-sensitive proliferation was desensitized in chronically activated T cells as well as in T cells activated once in the presence of the anti-CD4 mAb W3/25. Conversely, MBP responsiveness of W3/25-insensitive proliferation was unchanged by both chronic activation and by a prior activation in the presence of W3/25. In cultures of T cells recently activated by MBP in the presence of W3/25, the use of nonirradiated SPL rather than irradiated SPL reversed W3/25-mediated tolerance but did not restore MBP-stimulated IL-2 production. In summary, this study reveals mechanisms whereby the engagement of TcR and CD4 negatively regulates subsequent responsiveness of IL-2 production pathways and thereby impairs restimulation of IL-2-dependent proliferation by MBP-specific T-helper cells.
authors.affiliation: Department of Microbiology and Immunology, East Carolina University School of Medicine, Greenville, North Carolina 27858-4354.
authors.forename: M D
authors.initials: MD
authors.lastname: Mannie
authors.forename: H
authors.initials: H
authors.lastname: Truman
authors.forename: J
authors.initials: J
authors.lastname: Morrison-Plummer
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D015704:CD4 Antigens / Q000502:physiology*; D002460:Cell Line; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology; D006168:Guinea Pigs; D007376:Interleukin-2 / Q000096:biosynthesis*; D008213:Lymphocyte Activation; D004676:Myelin Basic Protein / Q000276:immunology*; D051381:Rats; D011917:Rats, Inbred Lew; D017634:Self Tolerance; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D007376:Interleukin-2; D004676:Myelin Basic Protein