THE UNFOLDED PROTEIN RESPONSE IN T CELL THYMIC DEVELOPMENT AND PERIPHERAL DIFFERENTIATION

The Unfolded Protein Response In T Cell Thymic Development And Peripheral DifferentiationAbstractbyBRENDAN M. BARTONEffector T cell differentiation involves coordination of transcription factor networks reinforced by signals integrated from their microenvironment. Herein, I demonstrate that the tripartite unfolded protein response (UPR) integrated signals in vitro downstream of T cell receptor signaling and co-stimulation and in vivo in response to viral infection. While mice with T cell specific deficiency of individual UPR enzymes mounted normal anti-viral responses, mice containing T cells devoid of all three UPR enzymes markedly failed to generate anti-viral T cell responses and exhibited early exhaustion. Transcriptome and epigenetic analysis revealed UPR-deficient CD4+ and CD8+ antiviral T cells failed to upregulate the Ets1-Id2 transcription factor network to promote chromatin accessibility at multiple effector gene loci. Re-expression of the transcription factor XBP1s downstream of UPR sensor IRE1α was sufficient to rescue these defects. Thus, I demonstrate the underlying compensation of UPR enzymes and an interdependent role of UPR sensors in T cell effector differentiation.