TY - JOUR
T1 - A Broad Range of Self-Reactivity Drives Thymic Regulatory T Cell Selection to Limit Responses to Self
AU - Lee, Hyang Mi
AU - Bautista, Jhoanne L.
AU - Scott-Browne, James
AU - Mohan, James F.
AU - Hsieh, Chyi Song
N1 - Funding Information:
We thank N. Santacruz and J. Hunn for technical assistance, W. Ise, K. Murphy, B. Helmink, and B. Sleckman for reagents; W. McCoy, D. Fremont, D. Donermeyer, and P.M. Allen for technical assistance and helpful discussions; and K. Murphy, T. Egawa, P.M. Allen, E. Unanue, C.W. Lio (all Wash. U), Y. Zheng (Salk), and L.F. Lu (UCSD) for helpful discussion and critical reading of the manuscript. This work was supported by the NIH (C.-S.H.).
PY - 2012/9/21
Y1 - 2012/9/21
N2 - The degree of T cell self-reactivity considered dangerous by the immune system, thereby requiring thymic selection processes to prevent autoimmunity, is unknown. Here, we analyzed a panel of T cell receptors (TCRs) with a broad range of reactivity to ovalbumin (OVA323-339) in the rat insulin promoter (RIP)-mOVA self-antigen model for their ability to trigger thymic self-tolerance mechanisms. Thymic regulatory T (Treg) cell generation in vivo was directly correlated with in vitro TCR reactivity to OVA-peptide in a broad ∼1,000-fold range. Interestingly, higher TCR affinity was associated with a larger Treg cell developmental "niche" size, even though the amount of antigen should remain constant. The TCR-reactivity threshold to elicit thymic negative selection and peripheral T cell responses was ∼100-fold higher than that of Treg cell differentiation. Thus, these data suggest that the broad range of self-reactivity that elicits thymic Treg cell generation is tuned to secure peripheral tolerance to self.
AB - The degree of T cell self-reactivity considered dangerous by the immune system, thereby requiring thymic selection processes to prevent autoimmunity, is unknown. Here, we analyzed a panel of T cell receptors (TCRs) with a broad range of reactivity to ovalbumin (OVA323-339) in the rat insulin promoter (RIP)-mOVA self-antigen model for their ability to trigger thymic self-tolerance mechanisms. Thymic regulatory T (Treg) cell generation in vivo was directly correlated with in vitro TCR reactivity to OVA-peptide in a broad ∼1,000-fold range. Interestingly, higher TCR affinity was associated with a larger Treg cell developmental "niche" size, even though the amount of antigen should remain constant. The TCR-reactivity threshold to elicit thymic negative selection and peripheral T cell responses was ∼100-fold higher than that of Treg cell differentiation. Thus, these data suggest that the broad range of self-reactivity that elicits thymic Treg cell generation is tuned to secure peripheral tolerance to self.
UR - http://www.scopus.com/inward/record.url?scp=84866524744&partnerID=8YFLogxK
U2 - 10.1016/j.immuni.2012.07.009
DO - 10.1016/j.immuni.2012.07.009
M3 - Article
C2 - 22921379
AN - SCOPUS:84866524744
VL - 37
SP - 475
EP - 486
JO - Immunity
JF - Immunity
SN - 1074-7613
IS - 3
ER -