The mechanisms controlling induction of anergy at the level of naïve CD4 ؉ T cells are poorly understood but thought to reflect limited contact with costimulatory molecules during T cell antigen receptor (TCR) ligation. To clarify this question, naïve TCR transgenic CD4 ؉ cells were exposed to specific peptide presented by transfected antigen-presenting cells (APC) expressing MHC class II molecules with defined accessory molecules. Significantly, culturing CD4 ؉ cells with APC expressing MHC II plus peptide alone elicited early TCR signaling but failed to induce either proliferation or anergy. Culture with APC expressing MHC II plus B7 molecules led to strong proliferation and T cell priming but no anergy. In marked contrast, conspicuous induction of anergy occurred after T cell culture with APC expressing MHC class II and intercellular adhesion molecule-1 (ICAM-1). Thus, at the level of naïve CD4 ؉ cells, anergy induction appears to reflect selective contact with APC expressing ICAM-1 in the absence of B7.rodent ͉ adhesion molecules T he outcome of initial T cell contact with antigen (immunity or tolerance) is important both for assuring adequate responses to infectious pathogens and preventing inappropriate responses to self-antigens. The mechanisms controlling self͞nonself discrimination are not fully understood but may hinge on the function of costimulatory molecules. For normal immune responses, it is clear that T cell stimulation involves not only T cell receptor (TCR) recognition of peptide-MHC complexes but also interactions between costimulatory receptors and their ligands on professional antigen-presenting cells (APC). CD28 molecules are the bestcharacterized costimulatory receptors on T cells. Binding of CD28 to its B7 ligands complements TCR ligation to promote immunological synapses between T cells and APC (1, 2) and ultimately the induction of sustained proliferative responses, cytokine production (e.g., IL-2 and IL-4), and expression of molecules promoting cell survival (e.g., Bcl-x L ) (3-8).When T cells recognize antigen in the absence of costimulation, however, the results are quite different. For primed T cells, TCR stimulation (signal 1) without concomitant coligation of CD28 (signal 2) induces T cell functional unresponsiveness or anergy characterized by the failure to proliferate or make IL-2 on reexposure to antigen presented in the context of optimal costimulation (8-12).Although this paradigm for anergy induction is well established for T cell clones and lines, there is considerable controversy as to whether delivery of signal 1 alone also induces anergy at the level of naïve CD4 ϩ T cells. In the studies of Lechler and colleagues (13), exposure of unprimed CD4 ϩ T cells to immobilized anti-CD3 mAb was shown to render the surviving cells profoundly unresponsive to subsequent mitogen stimulation. The relevance of this finding to physiological recognition of MHC-peptide on normal APC is somewhat unclear, because the affinity of the TCR for peptide-MHC complexes is more than 1,000-fold lowe...

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