title: Direct presentation regulates the magnitude of the CD8+ T cell response to cell-associated antigen through prolonged T cell proliferation.
abstract: The magnitude and complexity of Ag-specific CD8(+) T cell responses is determined by intrinsic properties of the immune system and extrinsic factors, such as vaccination. We evaluated mechanisms that regulate the CD8(+) T cell response to two distinct determinants derived from the same protein Ag, SV40 T Ag (T Ag), following immunization of C57BL/6 mice with T Ag-transformed cells. The results show that direct presentation of T cell determinants by T Ag-transformed cells regulates the magnitude of the CD8(+) T cell response in vivo but not the immunodominance hierarchy. The immunodominance hierarchy was reversed in a dose-dependent manner by addition of excess naive T cells targeting the subdominant determinant. However, T cell competition played only a minor role in limiting T cell accumulation under physiological conditions. We found that the magnitude of the T cell response was regulated by the ability of T Ag-transformed cells to directly present the T Ag determinants. The hierarchy of the CD8(+) T cell response was maintained when Ag presentation in vivo was restricted to cross-presentation, but the presence of T Ag-transformed cells capable of direct presentation dramatically enhanced T cell accumulation at the peak of the response. This enhancement was due to a prolonged period of T cell proliferation, resulting in a delay in T cell contraction. Our findings reveal that direct presentation by nonprofessional APCs can dramatically enhance accumulation of CD8(+) T cells during the primary response, revealing a potential strategy to enhance vaccination approaches.
authors.affiliation: Department of Microbiology and Immunology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Tatum
authors.forename: Alan M
authors.initials: AM
authors.lastname: Watson
authors.forename: Todd D
authors.initials: TD
authors.lastname: Schell
mesh_terms: D019264:Adoptive Transfer / Q000379:methods; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D000952:Antigens, Polyomavirus Transforming / Q000008:administration & dosage / Q000378:metabolism / Q000502:physiology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism* / Q000637:transplantation; D002460:Cell Line; D049109:Cell Proliferation; D002472:Cell Transformation, Viral / Q000276:immunology; D002478:Cells, Cultured; D003601:Cytotoxicity Tests, Immunologic / Q000379:methods; D018984:Epitopes, T-Lymphocyte / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism; D005260:Female; D007115:Immunization Schedule; D016056:Immunodominant Epitopes / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D013997:Time Factors
chemical_list: D000952:Antigens, Polyomavirus Transforming; D018984:Epitopes, T-Lymphocyte; D016056:Immunodominant Epitopes