Avidity of CD8 T cells sharpens immunodominance.
In the course of viral infection, the immune system exploits only a fraction of the available CTL repertoire and focuses on a few of a myriad of potentially antigenic peptides. This phenomenon, known as immunodominance, depends on a number of factors, including antigen processing and transport, MHC binding, competition for antigen-presenting cells, availability of the CD8 T cell repertoire and other mechanisms that function largely by restricting the immune response. Here we elucidate a novel mechanism that increases the immunodominance of the epitope rather by enhancing the immune response. Using a peptide-specific MHC-restricted mAb and functional assays of CTL activation, we show that T cells with high avidity for the immunodominant, H-2D(d) restricted, P18-I10 epitope expand rapidly following immunization, and this expansion in turn determines the level of the P18-I10 epitope immunodominance. This proliferation has little dependence on the number of MHC-peptide complexes. Since most self-reactive T cells of high avidity are depleted in the thymus, the selection of immunodominant epitopes based on the expansion of high-avidity T cells in the periphery reduces the potential for autoimmunity.
Dzutsev
Amiran H
AH
Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-1578, USA.
Belyakov
Igor M
IM
Isakov
Dmitry V
DV
Margulies
David H
DH
Berzofsky
Jay A
JA
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D002452:Cell Count; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D006183:H-2 Antigens / Q000276:immunology / Q000378:metabolism; D015699:HIV Envelope Protein gp120 / Q000276:immunology / Q000378:metabolism; D019302:HIV Envelope Protein gp160 / Q000235:genetics / Q000276:immunology; D064532:Histocompatibility Antigen H-2D; D016056:Immunodominant Epitopes / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D008285:Major Histocompatibility Complex / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D008815:Mice, Inbred Strains; D018448:Models, Immunological; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D014611:Vaccination / Q000379:methods; D014616:Vaccinia virus / Q000235:genetics
D006183:H-2 Antigens; D015699:HIV Envelope Protein gp120; D019302:HIV Envelope Protein gp160; D064532:Histocompatibility Antigen H-2D; D016056:Immunodominant Epitopes; C483883:P18-I10 peptide; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D007371:Interferon-gamma