Single dose of anti-CTLA-4 enhances CD8+ T-cell memory formation, function, and maintenance.

CTLA-4. an lg superfamily molecule with homology to CD28, is one of the most potent negative regulators of 1-cell responses. In vivo blockade of CTLA-4 exacerbates autoimmunity, enhances tumor specific 1-cell responses, and may inhibit the induction of T-cell anergy. Clinical trials of CTLA-4-blocking antibodies to augment T-cell responses to malignant melanoma are at an advanced stage; however, little is known about the effects of CTLA-4 blockade on memory CD8⁺ T-cell responses and the formation and maintenance of long-term CD8⁺ T-cell memory. In our studies, we show that during in vivo memory CD8⁺ T-ceIl responses to Listeria monocy- to genes infection, CTLA-4 blockade enhances bacterial clearance and increases memory CD8⁺ T-cell expansion. This is followed by an accumulation of memory cells that are capable of producing the effector cytokines IFN-γ and TNF-α. We also demonstrate that in a vaccination setting, blocking CTLA-4 during CD8⁺ T-cell priming leads to increased expansion and maintenance of antigen-specific memory CD8⁺ T-cells without adversely affecting the overall T-cell repertoire. This leads to an increase in memory cell effector function and improved protective immunity against further bacterial challenges. These results indicate that transient blockade of CTLA-4 enhances memory CD8⁺ T-cell responses and support the possible use of CTLA-4-blocking antibodies during vaccination to augment memory formation and maintenance. [ABSTRACT FROM AUTHOR]