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Single dose of anti-CTLA-4 enhances CD8+ T-cell memory formation, function, and maintenance.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2011 Jan 04; Vol. 108 (1), pp. 266-71. Date of Electronic Publication: 2010 Dec 20. - Publication Year :
- 2011
-
Abstract
- 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.
- Subjects :
- Adoptive Transfer
Animals
CD8-Positive T-Lymphocytes drug effects
CD8-Positive T-Lymphocytes microbiology
CTLA-4 Antigen
Cytokines biosynthesis
DNA-Binding Proteins genetics
Flow Cytometry
Immunologic Memory drug effects
Mice
Mice, Knockout
Antibodies, Monoclonal pharmacology
Antigens, CD immunology
CD8-Positive T-Lymphocytes immunology
Immunologic Memory immunology
Listeria monocytogenes immunology
Listeriosis immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 108
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 21173239
- Full Text :
- https://doi.org/10.1073/pnas.1016791108