How memory T cells are maintained in vivo is poorly understood. To address this problem, a male-specific peptide (H-Y) was identified and used to activate female anti-H-Y T cells in vitro.Anti-H-Y T cells survived in vivo for at least 70 days in the absence of antigen. This persistence was not because of the intrinsic ability of memory T cells to survive in vivo. Instead, the survival and function of adoptively transferred memory cells was found to require transporter of antigen protein 1-dependent expression of self-peptide͞major histocompatibility complex class I molecules in recipient animals. Therefore, it appears that the level of T cell receptor engagement provided by transporter of antigen protein 1-dependent, self-peptide͞major histocompatibility complexes is sufficient to maintain the long-term survival and functional phenotype of memory cells in the absence of persistent antigen. These data suggest that positive selection plays a role not only in T cell development but also in the maintenance of T cell memory.Immunological memory is a characteristic feature of the adaptive immune system and appears to result from the persistence of a heightened reactive state initiated by antigenic challenge. Secondary or memory responses are more rapid in onset and more effective than primary immune responses. The ability to generate a memory response protects organisms from recurrent challenge by pathogens. The means by which T cell memory is maintained is not completely understood. One model postulates that longterm memory is dependent on persistent antigenic stimulation (1, 2). According to this model small amounts of antigen, derived from an initial infection, persist in specialized depots, such as follicular dendritic cells, ensuring that a small subset of T cells is maintained in an activated state long after a pathogen is cleared. However, this view was challenged by the observation that T cells from virally immunized mice, when adoptively transferred to antigen-free animal hosts, gave rise to T cells that responded rapidly to antigen and retained the expression of activation markers (3-5). These results suggest that T cell memory may be because of the presence of long-lived memory cells, which are derived from antigen-activated cells and persist in the absence of antigen.Mature T cells express T cell receptors (TCRs), which are weakly reactive to self-peptide͞major histocompatibility complex (MHC) molecules as a result of thymic positive selection (6, 7). Thus, memory T cells could persist not because they have an inherently longer life-span, but because they receive constant low level stimulation from the same self-peptide͞MHC molecules that provide the signaling for positive selection during development. The expression of the self-peptide͞MHC complexes that trigger positive selection of CD8 ϩ T cells are largely dependent on the expression of TAP1 (transporter of antigen protein 1) (8, 9). The TAP1 gene encodes an ATP-dependent peptide pump (10), which translocates peptides from the cytosol into the...

To understand how thymic selection gives rise to T cells that are capable of major histocompatibility complex (MHC)-restricted recognition of antigen but are tolerant of self, we directly examined how peptide/MHC ligands expressed on thymic epithelial cells trigger the positive selection of immature thymocytes. We demonstrate that abundant self-peptides, purified from the H-2D(b) molecules of thymic epithelial cells, are specifically recognized during the positive selection of CD8+ T cells, implying that positive selection generates a repertoire of T cells that is weakly self-reactive. We also found that this recognition is somewhat cross-reactive, thereby providing an explanation for how the specific recognition of a limited repertoire of thymic self-peptides can select a diverse repertoire of T cells.

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Red blood cells (RBC) have emerged as a novel regulatory cell type endowed with bioactivities toward activated human T cells. Herein we show that the RBC bioactivities act on intracellular pathways initiated by T cell receptor (TCR)-dependent and -independent stimuli,including IL-2, IL-15, and the mixture of phorbol dibutyrate and ionomycin. The RBC bioactivities preserve the antioxidant status and are capable of rescuing activated T cells from cell death induced by serum deprivation. They are not mediated by glycosylphosphatidylinositol-linked receptors or sialic acids, and kinetic studies revealed that they hasten the entrance into the cell cycle. By using cyclosporine A (CsA) and rapamycin (Rapa) we show that the RBC bioactivities are calcineurin-dependent. Thus, treatment of T cells with CsA, but not Rapa, impaired RBC bioactivities, and preincubation of RBC with CsA completely abolished their bioactivities. We have demonstrated that RBC carry out bioactivities that are sensitive to CsA.

It has been postulated that the critical feature that determines the developmental fate of an immature thymocyte is the avidity of interaction between thymocyte TCR and peptide/MHC molecules on thymic stromal cells. However, it is possible that certain innate properties of peptides predispose them to triggering only positive or negative selection irrespective of their density on thymic stromal cells. To distinguish between these hypotheses, we examined the ability of several different peptides to induce the positive and negative selection of TCR transgenic (P14) antilymphocytic choriomeningitis virus (LCMV) CTLs in fetal thymus organ cultures (FTOC) from TAP1+ and TAP1- mice. We found that only relatively weak agonist peptides could induce the positive selection of anti-LCMV CTLs. A nonagonist peptide could induce positive selection but not negative selection; however, a weak agonist peptide could induce the positive selection of anti-LCMV CTLs in P14 TAP1- FTOC and negative selection in P14 TAP1+ FTOC. These data imply that there are upper and lower limits for the affinity of a peptide in triggering positive or negative selection, but that for peptides of intermediate affinity the overall avidity of interaction with the P14 TCR is the critical parameter in determining the developmental fate of thymocytes. Our observations also suggest a prominent role for low affinity self peptides in selecting a function repertoire of CD8+ T cells.