Recurrent superantigen exposure in vivo leads to highly suppressive CD4+CD25+ and CD4+CD25- T cells with anergic and suppressive genetic signatures.
Staphylococcal enterotoxin B (SEB) activates T cells via non-canonical signalling through the T cell receptor and is an established model for T cell unresponsiveness in vivo. In this study, we sought to characterize the suppressive qualities of SEB-exposed CD4(+) T cells and correlate this with genetic signatures of anergy and suppression. SEB-exposed CD25(+) and CD25(-)Vbeta8(+)CD4(+) T cells expressed forkhead box P3 (FoxP3) at levels comparable to naive CD25(+) T regulatory cells and were enriched after exposure in vivo. Gene related to anergy in lymphocytes (GRAIL), an anergy-related E3 ubiquitin ligase, was up-regulated in the SEB-exposed CD25(+) and CD25(-)FoxP3(+)Vbeta8(+)CD4(+) T cells and FoxP3(-)CD25(-)Vbeta8(+)CD4(+) T cells, suggesting that GRAIL may be important for dominant and recessive tolerance. The SEB-exposed FoxP3(+)GRAIL(+) T cells were highly suppressive and non-proliferative independent of CD25 expression level and via a glucocorticoid-induced tumour necrosis factor R-related protein-independent mechanism, whereas naive T regulatory cells were non-suppressive and partially proliferative with SEB activation in vitro. Lastly, adoptive transfer of conventional T cells revealed that induction of FoxP3(+) regulatory cells is not operational in this model system. These data provide a novel paradigm for chronic non-canonical T cell receptor engagement leading to highly suppressive FoxP3(+)GRAIL(+)CD4(+) T cells.
Schartner
J M
JM
Department of Pediatrics, University of Wisconsin, Madison, WI 53792-4108, USA.
Singh
A M
AM
Dahlberg
P E
PE
Nettenstrom
L
L
Seroogy
C M
CM
D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D017635:Clonal Anergy; D004768:Enterotoxins / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000378:metabolism; D053450:Glucocorticoid-Induced TNFR-Related Protein; D007108:Immune Tolerance; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis; D051379:Mice; D008807:Mice, Inbred BALB C; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D018089:Superantigens / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology
D004768:Enterotoxins; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053450:Glucocorticoid-Induced TNFR-Related Protein; C508018:Il2ra protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; D018089:Superantigens; C491405:TNFRSF18 protein, human; C031818:enterotoxin B, staphylococcal; C520250:RNF128 protein, human; D044767:Ubiquitin-Protein Ligases