T-Helper Lymphocytes Specific for Myelin Basic Protein: Low-Density Activation Prolongs a Postactivation Refractory Phase Marked by Decreased Pathogenicity and Enhanced Sensitivity to Anergy

Regulation of experimental autoimmune encephalomyelitis (EAE) in Lewis rats may involve activation-dependent negative feedback pathways of T-helper cells. Previous studies have shown that T-helper cells specific for myelin basic protein exhibit a postactivation refractory phase during which antigenic restimulation elicits proliferation without production of IL-2. Herein, we show that postactivation refractoriness inhibits regeneration of EAE transfer activity and is manifest by a lack of IL-2 mRNA accumulation despite induction of normal levels of IL-4 mRNA. Preactivated refractory T cells were substantially more susceptible than resting T cells to the induction of anergy. Low-density T cell activation or subcloning prolonged the duration of the refractory phase and engendered long-term desensitization of T cells marked by a blockade of IL-2 production and by enhanced susceptibility to anergy. Overall, these results support the concept that postactivation refractoriness controls the pathogenicity and differentiation of T-helper cells.