Distinct influences of peptide-MHC quality and quantity on in vivo T-cell responses.
The strength of T-cell receptor (TCR) stimulation and subsequent T-cell response depend on a combination of peptide-major histocompatibility complex (pMHC) density and potency. By comparing two different pMHC at doses yielding similar proliferation in vivo, we have highlighted unexpected differences in the qualitative and quantitative effects of TCR ligand. Measurements of cytokine sensitivity and two-photon imaging of T cell-dendritic cell (T-DC) interactions reveal discrimination between comparably weak stimuli resulting from either decreased pMHC potency or pMHC density. In addition, TCR-induced genes in broad gene expression profiles segregate into two groups: one that responds to cumulative TCR signal and another that responds to pMHC quality, independent of quantity. These observations suggest that models of TCR ligand discrimination must account for disparate sensitivity of downstream responses to specific influences of pMHC potency.
Department of Immunology, Howard Hughes Medical Institute, and Ludwig Center for Cancer Immunotherapy, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Rachel A
RA
Gottschalk
Matthew M
MM
Hathorn
Hélène
H
Beuneu
Emily
E
Corse
Michael L
ML
Dustin
Grégoire
G
Altan-Bonnet
James P
JP
Allison
D000818:Animals; D002450:Cell Communication / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects; D006649:Histocompatibility Antigens / Q000276:immunology*; D007376:Interleukin-2 / Q000494:pharmacology; D008297:Male; D051379:Mice; D010455:Peptides / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D015375:Receptors, Interleukin-2 / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000276:immunology*
D006649:Histocompatibility Antigens; D007376:Interleukin-2; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D015375:Receptors, Interleukin-2