Delayed expansion of a restricted T cell repertoire by low-density TCR ligands.
The role of TCR ligand density (i.e. the number of antigen-MHC complexes) in modulating the diversity of a T cell response selected from a pool of naive precursors remains largely undefined. By measuring early-activation markers up-regulation and proliferation following stimulation with staphylococcal enterotoxin A (SEA), we demonstrate that decreasing the ligand dose below an optimal concentration leads to the delayed activation of a restricted set of TCRVbeta-bearing T cells, with the specific, non-stochastic exclusion of some TCRVbeta+ T cells from the activated pool. Our results suggest that the failure of these TCRVbeta-bearing T cells to reach the activation threshold at sub-optimal ligand concentration is due to the inefficiency of TCR engagement, as measured by TCR internalization, and does not correlate with the relative precursor frequency in the non-immune repertoire. Moreover, even at SEA concentrations that lead to the simultaneous proliferation of all SEA-reactive T cells, we observe marked differences in the ability to secrete cytokines among the different responsive TCRVbeta-bearing T cells. Altogether, our results indicate that the development of a T cell response to a scarce display of ligand significantly narrows TCR repertoire diversity by mechanisms that involve focusing of the repertoire on the expansion of those T cells with the highest avidity of TCR engagement.
Laboratoire d'Immunologie, Centre de recherche du Centre Hospitalier de l'Université de Montréal, Hôpital Saint-Luc, Montréal, Québec H2X 1P1, Canada.
Pascal M
PM
Lavoie
Alain R
AR
Dumont
Helen
H
McGrath
Anne-Elen
AE
Kernaleguen
Rafick-P
RP
Sékaly
D017951:Antigen Presentation / Q000187:drug effects* / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004306:Dose-Response Relationship, Immunologic; D004768:Enterotoxins / Q000494:pharmacology*; D015329:Gene Rearrangement, T-Lymphocyte / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D007369:Interferon Inducers / Q000494:pharmacology*; D008024:Ligands; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta; D013601:T-Lymphocytes / Q000276:immunology*
D004768:Enterotoxins; D007369:Interferon Inducers; D008024:Ligands; D016693:Receptors, Antigen, T-Cell, alpha-beta; C026066:enterotoxin A, Staphylococcal