Thymic Selection Generates T Cells Expressing Self-Reactive TCRs in the Absence of CD45

Abstract

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 BWα−β− 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.

Identification of potential genomic biomarkers for Sjögren’s syndrome using data pooling of gene expression microarrays

“…PTPRC seems to modulate signaling mediated by the T cell receptor, alter thymic selection processes, and shape the T cell repertoire. Therefore, PTPRC may be contributing to susceptibility to autoimmune diseases [37].…”

CD45 regulates thymocyte survival during development in fetal thymic organ culture

“…CD45 knock-out (CD45À/À) mice exhibit a block at the double negative (DN) to double positive (DP) stage as well as a major block at the DP to single positive (SP) transition (Byth et al 1996). These CD45-deficient mice exhibit defects in both positive (Byth et al 1996;Mee et al 1999) and negative (Ogilvy et al 2003) selection leading to the production of a very limited and selfreactive T cell population (Trop et al 2000).…”

Immune Ontogeny and Engraftment Receptivity in the Sheep Fetus

“…. imprinting and memory that are gestational age-dependent and involve CD45 modulation [27] . As B-cell tolerance is noted following gene transplantation during the engraftment window and early differentiation (expression of CD45) of B cells is evident in the thymus, we believe the most likely mechanism to account for B-cell tolerance following fetal transplantation is thymic imprinting of deletional memory into the B lineage as well as the T lineage.…”