Modulation of  Thymic Selection by Expression of an Immediate-early Gene Early Growth Response 1 (Egr-1)

摘要

The potential involvement of early growth response (Egr)-1, a zinc-finger transcription factor belonging to the immediate-early genes, in positiveegative selection of thymocytes has been implicated by its expression in the population of CD4⁺CD8⁺ double positive (DP) cells undergoing selection. To further investigate this possibility, transgenic mice overexpressing Egr-1 in thymocytes were bred with a transgenic mouse line expressing a T cell receptor (TCR) recognizing the H-Y male antigen in the context of H-2^b class I major histocompatibility complex (MHC) molecules. In Egr-1/TCR H-Y double-transgenic mice, efficient positive selection of H-Y CD8⁺ T cells occurred, even in mice on either a nonselecting H-2^d background or a β2-microglobulin (β2m)-deficient background in which the expression of class I MHC heavy chains is extremely low; no positive selection was observed on a K^b−/−D^b−/−β2m^−/− background where class I MHC expression is entirely absent. Similarly, when the Egr-1 transgene was introduced into a class II MHC–restricted TCR transgenic mouse line, Egr-1/TCR double-transgenic mice revealed increased numbers of CD4⁺ T cells selected by class II MHC, as well as significant numbers of CD8⁺ T cells selected by class I MHC (for which the transgenic TCR might have weak affinity). Thus, Egr-1 overexpression allows positive selection of thymocytes via TCR–MHC interactions of unusually low avidity, possibly by lowering the threshold of avidity required for positive selection. Supporting this possibility, increased numbers of alloreactive T cells were positively selected in Egr-1 transgenic mice, resulting in a strikingly enhanced response against allo-MHC. These results suggest that expression of Egr-1 and/or its target gene(s) may directly influence the thresholds required for thymocyte selection.