Antigen-experienced T cells undergo a transient phase of unresponsiveness following optimal stimulation

Interaction of the Ag-specific receptor of T lymphocytes with its Ag/MHC li gand can lead either to cell activation or to a state of unresponsiveness o ften referred to as anergy, It has been generally assumed that anergy devel ops as a consequence of inadequate stimulation, such as in response to alte red peptide ligands or to agonists presented by costimulatory-deficient acc essory cells. The present study uncovers an alternative way of inducing an unresponsive state in T cells. Indeed, we demonstrate herein that Ag-stimul ation of murine CD4(+) Th clones induces cellular activation, characterized by cytokine production and cell proliferation, followed by a state of tran sient (lasting up to 6 days) unresponsiveness to further antigenic stimulat ion. This state of activation-induced unresponsiveness 1) is not a conseque nce of inadequate costimulation, as it occurs when cells are stimulated in the presence of dendritic cells or anti-CD28 Abs; 2) develops after an opti mal response to Ag; 3) is not due to cell death/apoptosis or CTLA-4 engagem ent; 4) down-regulates the proliferation and cytokine production of both Th 1- and Th2-like clones; and 5) does not affect the early steps of signal tr ansduction, Finally, naive T cells are not sensitive to this novel form of unresponsiveness, but become gradually susceptible to activation-induced un responsiveness upon Ag stimulation. Collectively, these data suggest that a ctivation-induced T cell unresponsiveness may represent a regulatory mechan ism limiting the clonal expansion and effector cell function of Ag-experien ced T cells, thus contributing to the homeostasis of an immune response.