MODULATION OF THYMIC SELECTION BY EXPRESSION OF AN IMMEDIATE-EARLY GENE, EARLY-GROWTH-RESPONSE-1 (EGR-1)

The potential involvement of early growth response (Egr)-1, a zinc-fin ger transcription factor belonging to the immediate-early genes, in po sitive/negative selection of thymocytes has been implicated by its exp ression in the population of CD4(+)CD8(+) double positive (DP) cells u ndergoing selection. To further investigate this possibility, transgen ic mice overexpressing Egr-1 in thymocytes were bred with a transgenic mouse line expressing a T cell receptor (TCR) recognizing the H-Y mal e antigen in the context of H-2(b) class I major histocompatibility co mplex (MHC) molecules. In Egr-1/TCR H-Y double-transgenic mice, effici ent positive selection of H-Y CD8(+) T cells occurred, even in mice on either a nonselecting H-2(d) background or a beta 2-microglobulin (be ta 2m)-deficient background in which the expression of class I MHC hea vy chains is extremely low; no positive selection was observed on a K( b-/-)Db(-/-)beta 2m(-/-) background where class I MHC expression is en tirely 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 or CD8(+) T cells sel ected by class I MHC (for which the transgenic TCR might have weak aff inity). Thus, Egr-1 overexpression allows positive selection of thymoc ytes via TCR-MHC interactions of unusually low avidity, possibly by lo wering the threshold of avidity required for positive selection. Suppo rting this possibility, increased numbers of alloreactive T cells were positively selected in Egr-1 transgenic mice, resulting in a striking ly enhanced response against allo-MHC. These results suggest that expr ession of Egr-1 and/or its target gene(s) may directly influence the t hresholds required for thymocyte selection.