[PDF][PDF] The emerging role of CTLA-4 as an immune attenuator

CB Thompson, JP Allison - Immunity, 1997 - cell.com
CB Thompson, JP Allison
Immunity, 1997cell.com
A variety of mechanisms were offered to account for this phenotype, including the possibility
that deletion In recent years, a great deal has been learned about of CTLA-4 resulted in the
failure of negative selection. how a T cell–dependent immune response is initiated.
According to this model, autoreactive T cells that had Activation of a naive T cell requires the
engagement of escaped negative selection in the thymus would emiits antigen-specific T
cell receptor (TCR) by a peptide grate and lymphoproliferation would be initiated upon …
A variety of mechanisms were offered to account for this phenotype, including the possibility that deletion In recent years, a great deal has been learned about of CTLA-4 resulted in the failure of negative selection. how a T cell–dependent immune response is initiated. According to this model, autoreactive T cells that had Activation of a naive T cell requires the engagement of escaped negative selection in the thymus would emiits antigen-specific T cell receptor (TCR) by a peptide grate and lymphoproliferation would be initiated upon antigen bound to a major histocompatibility complex their encounter with self-antigens in the periphery. Con-(MHC) protein. This interaction confers antigen specific- sistent with this model, a diminution of double-positive ity to a T cell response. Only T cells expressing a TCR thymocytes and a concomitant increase in the absolute that can bind a given antigen/MHC complex will re- number and frequency of single-positive thymocytes spond. However, under most circumstances, occupancy were observed in morbid animals. However, T cell develof the TCR is insufficient to initiate a productive T cell opment in the thymus of CTLA-4–deficient mice proresponse. A successful immune response usually re- ceeds normally even after the lymphoproliferation in the quires the engagement of additional costimulatory re- periphery is far advanced (Chambers et al., 1997). Alceptors. The best-characterized costimulatory receptor though at present it is not possible to rule out the possiexpressed on a resting T cell is CD28. Interaction of bility that negative selection has failed, current data do CD28 with its ligands expressed on the antigen-pre- not support a role for aberrant thymic development in senting cell (APC) plays a critical role in augmenting the pathogenesis of the lymphoproliferative disease in CTLA-4–deficient mice. Instead, the developmental data and sustaining a T cell response initiated through TCR together with the in vitro functional studies support the engagement. hypothesis that CTLA-4 plays an essential role in the CD28 shares its ligands, B7-1 and B7-2, with a related down-regulation of peripheral T cell responses. receptor, CTLA-4 (Figure 1). It has become apparent
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