TY - JOUR
T1 - TCR affinity and tolerance mechanisms converge to shape T cell diabetogenic potential
AU - Bettini, Maria
AU - Blanchfield, Lori
AU - Castellaw, Ashley
AU - Zhang, Qianxia
AU - Nakayama, Maki
AU - Smeltzer, Matthew P.
AU - Zhang, Hui
AU - Hogquist, Kristin A.
AU - Evavold, Brian D.
AU - Vignali, Dario A.A.
PY - 2014/7/15
Y1 - 2014/7/15
N2 - Autoreactive T cells infiltrating the target organ can possess a broad TCR affinity range. However, the extent to which such biophysical parameters contribute to T cell pathogenic potential remains unclear. In this study, we selected eight InsB9-23-specific TCRs cloned from CD4+ islet-infiltrating T cells that possessed a relatively broad range of TCR affinity to generate NOD TCR retrogenic mice. These TCRs exhibited a range of two-dimensional affinities (∼10-4-10-3 μm 4) that correlated with functional readouts and responsiveness to activation in vivo. Surprisingly, both higher and lower affinity TCRs could mediate potent insulitis and autoimmune diabetes, suggesting that TCR affinity does not exclusively dictate or correlate with diabetogenic potential. Both central and peripheral tolerance mechanisms selectively impinge on the diabetogenic potential of high-affinity TCRs, mitigating their pathogenicity. Thus, TCR affinity and multiple tolerance mechanisms converge to shape and broaden the diabetogenic T cell repertoire, potentially complicating efforts to induce broad, long-term tolerance.
AB - Autoreactive T cells infiltrating the target organ can possess a broad TCR affinity range. However, the extent to which such biophysical parameters contribute to T cell pathogenic potential remains unclear. In this study, we selected eight InsB9-23-specific TCRs cloned from CD4+ islet-infiltrating T cells that possessed a relatively broad range of TCR affinity to generate NOD TCR retrogenic mice. These TCRs exhibited a range of two-dimensional affinities (∼10-4-10-3 μm 4) that correlated with functional readouts and responsiveness to activation in vivo. Surprisingly, both higher and lower affinity TCRs could mediate potent insulitis and autoimmune diabetes, suggesting that TCR affinity does not exclusively dictate or correlate with diabetogenic potential. Both central and peripheral tolerance mechanisms selectively impinge on the diabetogenic potential of high-affinity TCRs, mitigating their pathogenicity. Thus, TCR affinity and multiple tolerance mechanisms converge to shape and broaden the diabetogenic T cell repertoire, potentially complicating efforts to induce broad, long-term tolerance.
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U2 - 10.4049/jimmunol.1400043
DO - 10.4049/jimmunol.1400043
M3 - Article
C2 - 24943217
AN - SCOPUS:84904253972
SN - 0022-1767
VL - 193
SP - 571
EP - 579
JO - Journal of Immunology
JF - Journal of Immunology
IS - 2
ER -