Longevity of antigen presentation and activation status of APC are decisive factors in the balance between CTL immunity versus tolerance

TY - JOUR

T1 - Longevity of antigen presentation and activation status of APC are decisive factors in the balance between CTL immunity versus tolerance

AU - den Boer, A T

AU - Diehl, L

AU - van Mierlo, G J

AU - van der Voort, E I

AU - Fransen, M F

AU - Krimpenfort, P

AU - Melief, C J

AU - Offringa, R

AU - Toes, R E

PY - 2001/9/1

Y1 - 2001/9/1

N2 - Encounter of Ag by naive T cells can lead to T cell priming as well as tolerance. The balance between immunity and tolerance is controlled by the conditions of Ag encounter and the activation status of the APC. We have investigated the rules that govern this balance in case an environment that normally induces tolerance is reverted into a milieu that promotes T cell priming, using a minimal CTL epitope derived from human adenovirus type 5 E1A. Vaccination of mice s.c. with E1A peptide in IFA readily induces CTL tolerance, resulting in the inability to control E1A-expressing tumors. The present study shows that efficient CTL priming is achieved when this peptide vaccine is combined with systemic administration of APC-activating compounds like agonistic anti-CD40 mAb or polyriboinosinate-polyribocytidylate. Surprisingly, this CTL response is not long-lasting and therefore fails to protect against tumor outgrowth. Disappearance of CTL reactivity was strongly associated with systemic persistence of the peptide for >200 days. In contrast, peptide administered in PBS does not persist and generates long term CTL immunity capable of rejecting Ad5E1A-positive tumors, when combined with CD40 triggering. Thus, presentation of CTL epitopes in an appropriate costimulatory setting by activated APC, although being essential and sufficient for CTL priming, eventually results in tolerance when the Ag persists systemically for prolonged times. These observations are important for the development of immune intervention schemes in autoimmunity and cancer.

AB - Encounter of Ag by naive T cells can lead to T cell priming as well as tolerance. The balance between immunity and tolerance is controlled by the conditions of Ag encounter and the activation status of the APC. We have investigated the rules that govern this balance in case an environment that normally induces tolerance is reverted into a milieu that promotes T cell priming, using a minimal CTL epitope derived from human adenovirus type 5 E1A. Vaccination of mice s.c. with E1A peptide in IFA readily induces CTL tolerance, resulting in the inability to control E1A-expressing tumors. The present study shows that efficient CTL priming is achieved when this peptide vaccine is combined with systemic administration of APC-activating compounds like agonistic anti-CD40 mAb or polyriboinosinate-polyribocytidylate. Surprisingly, this CTL response is not long-lasting and therefore fails to protect against tumor outgrowth. Disappearance of CTL reactivity was strongly associated with systemic persistence of the peptide for >200 days. In contrast, peptide administered in PBS does not persist and generates long term CTL immunity capable of rejecting Ad5E1A-positive tumors, when combined with CD40 triggering. Thus, presentation of CTL epitopes in an appropriate costimulatory setting by activated APC, although being essential and sufficient for CTL priming, eventually results in tolerance when the Ag persists systemically for prolonged times. These observations are important for the development of immune intervention schemes in autoimmunity and cancer.

KW - Adenovirus E1A Proteins

KW - Animals

KW - Antigen Presentation

KW - Antigen-Presenting Cells

KW - Antigens, CD40

KW - Humans

KW - Immune Tolerance

KW - Kinetics

KW - Lymphocyte Activation

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Transgenic

KW - Neoplasms, Experimental

KW - Receptors, Antigen, T-Cell, alpha-beta

KW - T-Lymphocytes, Cytotoxic

M3 - SCORING: Journal article

C2 - 11509591

VL - 167

SP - 2522

EP - 2528

JO - J IMMUNOL

JF - J IMMUNOL

SN - 0022-1767

IS - 5

ER -