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-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-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 beta2-microglobulin (beta2m)-deficient background in which the expression of class I MHC heavy chains is extremely low; no positive selection was observed on a Kb-/-Db-/-beta2m-/- 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.
Miyazaki
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Basel Institute for Immunology, CH-4005 Basel, Switzerland. miyazaki@bii.ch
Lemonnier
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D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D051766:Early Growth Response Protein 1; D005260:Female; D006183:H-2 Antigens / Q000502:physiology; D006182:H-Y Antigen / Q000096:biosynthesis / Q000235:genetics; D064532:Histocompatibility Antigen H-2D; D017874:Immediate-Early Proteins; D019891:Leukopoiesis / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D013950:Thymus Gland / Q000166:cytology* / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D016335:Zinc Fingers / Q000502:physiology*; D001613:beta 2-Microglobulin / Q000502:physiology
D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D006183:H-2 Antigens; D006182:H-Y Antigen; D064532:Histocompatibility Antigen H-2D; D017874:Immediate-Early Proteins; D014157:Transcription Factors; D001613:beta 2-Microglobulin