Regulatory T cells are resistant to apoptosis via TCR but not P2X7.
Regulatory T cells (Tregs) are relatively autoreactive yet, paradoxically, have been found to display normal sensitivity to thymic deletion. The relationship between self-avidity, apoptosis, and the selection of Tregs therefore remains unclear. We show that thymic Tregs develop efficiently, even at low self-avidity, and are moderately resistant to apoptosis in comparison to conventional thymocytes. Consistent with this, although conventional self-reactive T cell populations undergo chronic peripheral deletion, self-reactive Tregs are largely spared removal. Similarly, the distribution of Tregs among peripheral CD4(+) cells exhibits a linear inverse relationship with CD45RB expression, indicating relative apoptosis resistance of Tregs in chronic responses to environmental Ags. We also show that appropriate controls for CD45RB levels are important for comparisons of Treg and conventional T cell activity. When thus controlled, and contrary to previous reports, Tregs exhibit normal sensitivity to cell death through TCR-independent stimuli, such as the purinergic receptor, P2X(7). Finally, although absence of CD45 in gene-targeted mice results in profound T cell hyporesponsiveness, there is little or no effect on thymic Treg frequency. In summary, the data support a model in which signal strength plays little part in Treg lineage specification, though moderate resistance of self-reactive Tregs to apoptosis may result in progressive biasing of peripheral Treg TCRs toward autoreactivity in comparison to those of conventional T cells.
Taylor
Simon R J
SR
Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College, Hammersmith Hospital Campus, Du Cane Road, London, U.K.
Alexander
Denis R
DR
Cooper
Joanne C
JC
Higgins
Christopher F
CF
Elliott
James I
JI
D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D015551:Autoimmunity; D017493:Leukocyte Common Antigens / Q000276:immunology; D051379:Mice; D018448:Models, Immunological; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D018048:Receptors, Purinergic P2 / Q000276:immunology*; D058486:Receptors, Purinergic P2X7; D015398:Signal Transduction / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*
C546469:P2rx7 protein, mouse; D011948:Receptors, Antigen, T-Cell; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; D017493:Leukocyte Common Antigens