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J. Exp. Med.,
Volume 188, Number 4, August 17, 1998 715-723
By
From the * Basel Institute for Immunology, CH-4005 Basel, Switzerland; and the The potential involvement of early growth response (Egr)-1, a zinc-finger transcription factor
belonging to the immediate-early genes, in positive/negative 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-2b 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-2d background or a Unité d'Immunité
Cellulaire Antivirale, Institut Pasteur, 75724 Paris-Cedex 15, France
2-microglobulin (2m)-deficient background in which the expression of class I MHC heavy
chains is extremely low; no positive selection was observed on a Kb
/Db/2m/ 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.
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