TY - JOUR
T1 - Single dose of anti-CTLA-4 enhances CD8+ T-cell memory formation, function, and maintenance
AU - Pedicord, Virginia A.
AU - Montalvo, Welby
AU - Leiner, Ingrid M.
AU - Allison, James P.
PY - 2011/1/4
Y1 - 2011/1/4
N2 - CTLA-4, an Ig superfamily molecule with homology to CD28, is one of the most potent negative regulators of T-cell responses. In vivo blockade of CTLA-4 exacerbates autoimmunity, enhances tumor-specific T-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-cell responses to Listeria monocytogenes 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.
AB - CTLA-4, an Ig superfamily molecule with homology to CD28, is one of the most potent negative regulators of T-cell responses. In vivo blockade of CTLA-4 exacerbates autoimmunity, enhances tumor-specific T-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-cell responses to Listeria monocytogenes 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.
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U2 - 10.1073/pnas.1016791108
DO - 10.1073/pnas.1016791108
M3 - Article
C2 - 21173239
AN - SCOPUS:78651072784
SN - 0027-8424
VL - 108
SP - 266
EP - 271
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 1
ER -