Hierarchical signaling thresholds determine the fates of naíve T cells: partial priming leads nai;ve T cells to unresponsiveness.
Differing conditions of antigen priming varying either the concentration or affinity of T cell receptor (TCR) ligands greatly alter T cell responses. Here, we demonstrate that antigen-specific CD4(+) nai;ve T cells primed with either altered peptide ligands (APLs) or a minimal concentration of antigen peptide become anergic without observable cell divisions. Transforming growth factor-beta1 (TGF-beta1) expression was induced 24h following in these stimulation conditions producing anergic cells. Productively stimulated nai;ve T cells expressed IL-2 to differentiate into T helper 1 (Th1) cells, secreting interferon-gamma (IFN-gamma) upon secondary antigen stimulation; T cells primed with an APL did not secrete either interleukin-4 (IL-4) or IFN-gamma, but expressed TGF-beta1 and Tob, a member of the anti-proliferative gene family. Therefore, T cell responses are regulated by TCR signaling depending on the extent of TCR engagement. These results suggest that partial antigen stimulation in the periphery can induce nai;ve CD4(+)T cell unresponsiveness.
Yamashiro
Hiromichi
H
Research Institute for Biological Sciences, Science University of Tokyo, 2669 Yamazaki, Noda City, 278-0022, Chiba, Japan.
Odani
Yo
Y
Hozumi
Nobumichi
N
Nakano
Naoko
N
D000818:Animals; D000941:Antigens / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002455:Cell Division; D016207:Cytokines / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D008024:Ligands; D051379:Mice; D008822:Mice, Transgenic; D010455:Peptides / Q000378:metabolism; D011485:Protein Binding; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000737:chemistry* / Q000378:metabolism*; D018417:Th1 Cells; D013997:Time Factors
D000941:Antigens; D016207:Cytokines; D007376:Interleukin-2; D008024:Ligands; D010455:Peptides; D007371:Interferon-gamma