Selective expression of the 21-kilodalton tyrosine-phosphorylated form of TCR zeta promotes the emergence of T cells with autoreactive potential.
T cells undergo negative selection in the thymus to eliminate potentially autoreactive cells. The signals generated through the alphabeta TCR following receptor interactions with peptide/MHC complexes in the thymus control these selection processes. Following receptor ligation, a fraction of the TCR zeta subunit appears as two distinct tyrosine-phosphorylated forms of 21 and 23 kDa (p21 and p23). Previous data have reported elevated levels of p21 in some murine models of autoimmunity. We have examined the contributions of both the p21 and p23 to T cell negative selection in the HY TCR-transgenic system using ITAM-substituted TCR zeta and CD3 epsilon transgenic mice. Expression of just p21, in the absence of p23, partially impairs negative selection of self-reactive HY-specific T cells. This results in the emergence of potentially autoreactive peripheral T cells and an elevated population of CD11b(+)B220(+) B cells in the spleen. These data clearly identify a specific and unique role for p21 during negative selection.
Pitcher
Lisa A
LA
Center for Immunology and Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Mathis
Meredith A
MA
Subramanian
Srividya
S
Young
Jennifer A
JA
Wakeland
Edward K
EK
Love
Paul E
PE
van Oers
Nicolai S C
NS
D000375:Aging / Q000235:genetics / Q000276:immunology; D000818:Animals; D001324:Autoantigens / Q000235:genetics / Q000276:immunology*; D016827:CD8 Antigens / Q000096:biosynthesis; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D049109:Cell Proliferation; D017637:Clonal Deletion / Q000235:genetics / Q000276:immunology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D005260:Female; D006182:H-Y Antigen / Q000235:genetics; D016130:Immunophenotyping; D007413:Intestinal Mucosa / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008970:Molecular Weight; D010766:Phosphorylation; D011948:Receptors, Antigen, T-Cell / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism*
D001324:Autoantigens; D016827:CD8 Antigens; C409469:CD8 antigen, alpha chain; C493957:Cdkn1a protein, mouse; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D006182:H-Y Antigen; D008565:Membrane Proteins; D011948:Receptors, Antigen, T-Cell; D016693:Receptors, Antigen, T-Cell, alpha-beta; C054979:antigen T cell receptor, zeta chain; D014443:Tyrosine