Peripheral "CD8 tuning" dynamically modulates the size and responsiveness of an antigen-specific T cell pool in vivo.
In this study, we suggest that CD8 levels on T cells are not static, but can change and, as a result, modulate CD8(+) T cell responses. We describe three models of CD8 modulation using novel weak-agonist (K1A) and super-agonist (C2A) altered peptide ligands of the HY smcy peptide. First, we used peripheral nonresponsive CD8(low) T cells produced after peripheral HY-D(b) MHC class I tetramer stimulation of female HY TCR transgenic and wild-type mice. Second, we used genetically lowered CD8(int) T cells from heterozygote CD8(+/0) mice. Finally, we used pre-existing nonresponsive CD8(low) T cells from male HY TCR transgenic mice. In CD8(low) and CD8(high) mice, presence of a lower level of CD8 greatly decreased the avidity of the peptide-MHC for HY TCR as reflected by avidity (K(D)) and dissociation constant (T(1/2)) measurements. All three models demonstrated that lowering CD8 levels resulted in the requirement for a higher avidity peptide-MHC interaction with the TCR to respond equivalently to unmanipulated CD8(high) T cells of the same specificity. Additionally, direct injections of wild-type HY-D(b) and C2A-D(b) tetramers into female HY TCR or female B6 mice induced a high frequency of peripheral nonresponsive CD8(low) T cells, yet C2A-D(b) was superior in inducing a primed CD8(+)CD44(+) memory population. The ability to dynamically modulate the size and responsiveness of an Ag-specific T cell pool by "CD8 tuning" of the T cell during the early phases of an immune response has important implications for the balance of responsiveness, memory, and tolerance.
Maile
Robert
R
Department of Microbiology and Immunology, University of North Carolina, Chapel Hill 27599, USA. robmaile@bellsouth.net
Siler
Catherine A
CA
Kerry
Samantha E
SE
Midkiff
Katherine E
KE
Collins
Edward J
EJ
Frelinger
Jeffrey A
JA
D000818:Animals; D016827:CD8 Antigens / Q000096:biosynthesis; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D002454:Cell Differentiation / Q000276:immunology*; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism*; D005260:Female; D006182:H-Y Antigen / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism; D008024:Ligands; D008213:Lymphocyte Activation / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010455:Peptides / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D012727:Sex Characteristics; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D023001:Transplantation Tolerance / Q000235:genetics
D016827:CD8 Antigens; D018984:Epitopes, T-Lymphocyte; D006182:H-Y Antigen; D008024:Ligands; D010455:Peptides; D011948:Receptors, Antigen, T-Cell