Thymic selection generates T cells expressing self-reactive TCRs in the absence of CD45.
The CD45 protein tyrosine phosphatase regulates Ag receptor signaling in T and B cells. In the absence of CD45, TCR coupling to downstream signaling cascades is profoundly reduced. Moreover, in CD45-null mice, the maturation of CD4+CD8+ thymocytes into CD4+CD8- or CD4-CD8+ thymocytes is severely impaired. These findings suggest that thymic selection may not proceed normally in CD45-null mice, and may be biased in favor of thymocytes expressing TCRs with strong reactivity toward self-MHC-peptide ligands to compensate for debilitated TCR signaling. To test this possibility, we purified peripheral T cells from CD45-null mice and fused them with the BWalpha-beta- thymoma to generate hybridomas expressing normal levels of TCR and CD45. The reactivity of these hybridomas to self or foreign MHC-peptide complexes was assessed by measuring the amount of IL-2 secreted upon stimulation with syngeneic or allogeneic splenocytes. A very high proportion (55%) of the hybridomas tested reacted against syngeneic APCs, indicating that the majority of T cells in CD45-null mice express TCRs with high avidity for self-MHC-peptide ligands, and are thus potentially autoreactive. Furthermore, a large proportion of TCRs selected in CD45-null mice (H-2b) were also shown to display reactivity toward closely related MHC-peptide complexes, such as H-2bm12. These results support the notion that modulating the strength of TCR-mediated signals can alter the outcome of thymic selection, and demonstrate that CD45, by molding the window of affinity/avidity for positive and negative selection, directly participates in the shaping of the T cell repertoire.
Trop
S
S
Division of Experimental Medicine, Department of Medicine, McGill University, Montréal, Québec, Canada.
Charron
J
J
Arguin
C
C
Lesage
S
S
Hugo
P
P
D000818:Animals; D001896:Boron Compounds; D015704:CD4 Antigens / Q000096:biosynthesis; D016827:CD8 Antigens / Q000096:biosynthesis; D002454:Cell Differentiation / Q000276:immunology; D002459:Cell Fusion / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000096:biosynthesis; D006825:Hybridomas / Q000276:immunology / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000096:biosynthesis / Q000235:genetics*; D008213:Lymphocyte Activation / Q000235:genetics; D008285:Major Histocompatibility Complex / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D010455:Peptides / Q000276:immunology / Q000378:metabolism; D010649:Phenylalanine / Q000031:analogs & derivatives*; D011948:Receptors, Antigen, T-Cell / Q000096:biosynthesis* / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D013950:Thymus Gland / Q000166:cytology* / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D014407:Tumor Cells, Cultured
D001896:Boron Compounds; D015704:CD4 Antigens; D016827:CD8 Antigens; D018984:Epitopes, T-Lymphocyte; D007376:Interleukin-2; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D010649:Phenylalanine; D017493:Leukocyte Common Antigens; C033685:4-boronophenylalanine