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A Role for MAPK in Feedback Inhibition of Tcrb Recombination¹

Department of Immunology, Duke University Medical Center, Durham NC 27710

The Tcrb locus is subject to a host of regulatory mechanisms that impart a strict cell and developmental stage-specific order to variable (V), diversity (D), and joining (J) gene segment recombination. The Tcrb locus is also regulated by allelic exclusion mechanisms, which restrict functional rearrangements to a single allele. The production of a functional rearrangement in CD4^–CD8^– double-negative (DN) thymocytes leads to the assembly of a pre-TCR and initiates signaling cascades that allow for DN to CD4⁺CD8⁺ double-positive (DP) differentiation, proliferation, and feedback inhibition of further V to DJ rearrangement. Feedback inhibition is believed to be controlled, in part, by the loss of V gene segment accessibility during the DN to DP transition. However, the pre-TCR signaling pathways that lead to the inactivation of V chromatin have not been determined. Because activation of the MAPK pathway is documented to promote DP differentiation in the absence of allelic exclusion, we characterized the properties of V chromatin within DP thymocytes generated by a constitutively active Raf1 (Raf-CAAX) transgene. Consistent with previous reports, we show that the Raf-CAAX transgene does not inhibit Tcrb recombination in DN thymocytes. Nevertheless, DP thymocytes generated by Raf-CAAX signals display normal down-regulation of V segment accessibility and normal feedback inhibition of the V to DJ rearrangement. Therefore, our results emphasize the distinct requirements for feedback inhibition in the DN and DP compartments. Although MAPK activation cannot impose feedback in DN thymocytes, it contributes to feedback inhibition through developmental changes that are tightly linked to DN to DP differentiation.