TY - JOUR
T1 - Crossreactive αβ T Cell Receptors Are the Predominant Targets of Thymocyte Negative Selection
AU - McDonald, Benjamin D.
AU - Bunker, Jeffrey J.
AU - Erickson, Steven A.
AU - Oh-Hora, Masatsugu
AU - Bendelac, Albert
N1 - Funding Information:
We thank P. Savage for providing Vβ3 and Vβ8.3 transgenic mice; A. Chervonsky for SV-40 transformed fibroblast cell lines; and D. Leclerc and M. Olson for cell sorting. B.D.M. and J.J.B. were supported by an NIH Medical Scientist Training Program grant T32GM007281. Research was supported by NIH RO1 AI038339 and by Digestive Diseases Research Center of Excellence P30DK42086.
Publisher Copyright:
© 2015 Elsevier Inc.
PY - 2015/11/17
Y1 - 2015/11/17
N2 - The precise impact of thymic positive and negative selection on the T cell receptor (TCR) repertoire remains controversial. Here, we used unbiased, high-throughput cloning and retroviral expression of individual pre-selection TCRs to provide a direct assessment of these processes at the clonal level in vivo. We found that 15% of random TCRs induced signaling and directed positive (7.5%) or negative (7.5%) selection, depending on strength of signal, whereas the remaining 85% failed to induce signaling or selection. Most negatively selected TCRs exhibited promiscuous crossreactivity toward multiple other major histocompatibility complex (MHC) haplotypes. In contrast, TCRs that were positively selected or non-selected were minimally crossreactive. Negative selection of crossreactive TCRs led to clonal deletion but also recycling into intestinal CD4-CD8β- intraepithelial lymphocytes (iIELs). Thus, broadly crossreactive TCRs arise at low frequency in the pre-selection repertoire but constitute the primary drivers of thymic negative selection and iIEL lineage differentiation.
AB - The precise impact of thymic positive and negative selection on the T cell receptor (TCR) repertoire remains controversial. Here, we used unbiased, high-throughput cloning and retroviral expression of individual pre-selection TCRs to provide a direct assessment of these processes at the clonal level in vivo. We found that 15% of random TCRs induced signaling and directed positive (7.5%) or negative (7.5%) selection, depending on strength of signal, whereas the remaining 85% failed to induce signaling or selection. Most negatively selected TCRs exhibited promiscuous crossreactivity toward multiple other major histocompatibility complex (MHC) haplotypes. In contrast, TCRs that were positively selected or non-selected were minimally crossreactive. Negative selection of crossreactive TCRs led to clonal deletion but also recycling into intestinal CD4-CD8β- intraepithelial lymphocytes (iIELs). Thus, broadly crossreactive TCRs arise at low frequency in the pre-selection repertoire but constitute the primary drivers of thymic negative selection and iIEL lineage differentiation.
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U2 - 10.1016/j.immuni.2015.09.009
DO - 10.1016/j.immuni.2015.09.009
M3 - Article
C2 - 26522985
AN - SCOPUS:84947444776
VL - 43
SP - 859
EP - 869
JO - Immunity
JF - Immunity
SN - 1074-7613
IS - 5
ER -