After antigenic stimulation in the context of "danger signals," naive T cells embark on a programmed, intense expansion phase to counteract the rapid proliferation of pathogens. During the first week of infection, responding T cells undergo > 1000-fold expansion, resulting in the development of large numbers of cells exhibiting potent effector function. As the pathogen (antigen) burden dwindles, a majority of the effectors generated are eliminated by apoptosis, resulting in the survival and maintenance of a small population of antigen-specific cells as long-term memory T cells. Depending on the infection studied, CD8+ T cells appear to differentiate through multiple pathways into resting and effector memory subsets, and require multiple cytokines and cell surface molecules for survival and proliferation. Once generated, the repertoire of memory T cells remains highly vulnerable to attrition during heterologous infections, where homeostatic forces drive deletions in T-cell memory pools to accommodate the entry of new memory T cells. This review will primarily focus on the factors that influence the generation, maintenance, and attrition of memory CD8+ T cells.
"Furthermore, adoptive transfer therapies involving tumor-antigen specific CD8+ T cells have shown cancer regression in clinical trials . Moreover, memory CD8+ T cells can vary in both magnitude and quality – and generating a central memory population with a high level expression of CD62L (TCM) yields longer lasting tumor regression compared to CD62L low effector memory cells (TEM) –. We have previously reported that the choice of vaccine adjuvant and/or vector can also differentially impact the proportion of the two types of memory CD8+ T cells; for example Listeria monocytogenes generates a predominant CD62Lhigh central memory cells . "
[Show abstract][Hide abstract] ABSTRACT: Central memory CD8(+) T cells expressing the adhesion molecule CD62L (L-selectin) are potent mediators of anti-cancer immunity due to their ability to proliferate extensively upon antigen re-stimulation. The interaction of selectin with its ligands mediates leukocyte rolling along high endothelial venules. Mice deficient in α(1,3) Fucosyltransferase IV and VII (FtDKO) lack functional L, P and E selectin ligands. Thus, we addressed whether the lack of selectin ligand interactions alters tumor protection by CD8(+) T cells in FtDKO mice. Listeria monocytogenes-OVA (LM-OVA) infection evoked potent OVA-specific CD8(+) T cells that proliferated and contracted at similar kinetics and phenotype in FtDKO and wild-type mice. Additionally, OVA-specific CD8(+) T cells in both mouse strains exhibited similar phenotypic differentiation, in vivo cytolytic activity and IFN-γ expression. However, FtDKO mice succumbed to B16-OVA tumors significantly earlier than wild-type mice. In contrast, FtDKO mice evoked strong recall memory CD8(+) T cell responses and protection to systemic LM-OVA re-challenge. The diminished tumor protection in FtDKO mice was not related to defective antigen presentation by dendritic cells or reduced proliferation of antigen-specific CD8(+) T cells. However, WT or FtDKO OVA-specific CD8(+) T cells showed significantly reduced ability to traffic to lymph nodes upon adoptive transfer into naïve FtDKO recipients. Furthermore, FtDKO OVA-specific CD8(+) T cells displayed poor ability to infiltrate tumors growing in WT mice. These results reveal that selectin ligand expression on host endothelium as well CD8(+) T cells may be important for their efficient and continued extravasation into peripheral tumors.
PLoS ONE 02/2012; 7(2):e32211. DOI:10.1371/journal.pone.0032211 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Archaeal ether glycerolipid vesicles (archaeosomes) efficiently deliver exogenous antigen for induction of humoral and cell-mediated immunity. Because induction of CD8 cytotoxic T cells is critical for protective vaccination against tumors, we compared the ability of various archaeosome lipid compositions to evoke a strong CD8 CTL response to entrapped antigen. Subcutaneous immunization of mice with ovalbumin (OVA) entrapped in all archaeosome lipid compositions evoked a primary (day 10) splenic CTL response indicating processing for MHC class I presentation. Interestingly, several polar lipid compositions from halophilic archaea were very potent to adjuvant this early CTL response. Despite this, the lytic units reduced substantially by weeks 6-7. More importantly, at >50 weeks, only Methanobrevibacter smithii and Thermoplasma acidophilum both rich in bipolar membrane-spanning caldarchaeols, demonstrated recall memory CTLs. Immunization of mice with OVA entrapped in M. smithii, Halobacterium salinarum or T. acidophilum vesicles provided prophylactic protection against challenge with OVA-expressing solid tumors at 6 weeks. Even a dose of 3 microg OVA in archaeosomes significantly delayed tumor growth. Tumor protection was also noted in a therapeutic design wherein OVA-archaeosomes were injected concurrent with the tumor challenge. Interestingly, antigen-free T. acidophilum but not antigen-free H. salinarum archaeosomes provided innate therapeutic protection. Vaccination with a CTL peptide epitope from the melanoma differentiation antigen, tyrosinase-related protein 2, in archaeosomes induced a protective CD8 response against B16OVA metastasis, indicating potential for targeting self, tumor antigens. Thus, lipid structural properties of archaea may differentially modulate primary, long-term and/or innate immunity, impacting adjuvant choice for vaccine design.
Journal of Drug Targeting 01/2003; 11(8-10):515-24. DOI:10.1080/10611860410001670044 · 2.74 Impact Factor
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