ABSTRACT
The transcription factors nuclear factor of activated T cells (NFAT) and activator protein 1 (AP-1; Fos-Jun) cooperate to promote the effector functions of T cells, but NFAT in the absence of AP-1 imposes a negative feedback program of T cell hyporesponsiveness (exhaustion). Here, we show that basic leucine zipper ATF-like transcription factor (BATF) and interferon regulatory factor 4 (IRF4) cooperate to counter T cell exhaustion in mouse tumor models. Overexpression of BATF in CD8+ T cells expressing a chimeric antigen receptor (CAR) promoted the survival and expansion of tumor-infiltrating CAR T cells, increased the production of effector cytokines, decreased the expression of inhibitory receptors and the exhaustion-associated transcription factor TOX and supported the generation of long-lived memory T cells that controlled tumor recurrence. These responses were dependent on BATF-IRF interaction, since cells expressing a BATF variant unable to interact with IRF4 did not survive in tumors and did not effectively delay tumor growth. BATF may improve the antitumor responses of CAR T cells by skewing their phenotypes and transcriptional profiles away from exhaustion and towards increased effector function.
Subject(s)
Basic-Leucine Zipper Transcription Factors/metabolism , CD8-Positive T-Lymphocytes/immunology , Interferon Regulatory Factors/metabolism , Lymphocytes, Tumor-Infiltrating/immunology , Neoplasms/immunology , Receptors, Chimeric Antigen/immunology , Animals , Cell Line, Tumor , Disease Models, Animal , Female , Humans , Male , Melanoma, Experimental , Mice , Mice, Inbred C57BL , Mice, Transgenic , NFATC Transcription Factors/metabolism , Neoplasm Recurrence, Local/immunology , Transcription Factor AP-1/metabolismABSTRACT
ERP experiments were conducted to analyze the underlying neural events when chess players make simple judgments of a board position. Fourteen expert players and 14 age-matched novices viewed, for each of four tasks, 128 unique positions on a mini (4 × 4) chess board each presented for 0.5 s. The tasks were to respond: (a) if white king was in check, (b) if black knight was present, (c) if white king was not in check, and (d) if no black knight was present. Experts showed an enhanced N2 with check targets and a larger P3 with knight targets, relative to novices. Expert-novice differences in posterior N2 began as early as 240 ms on check-related searches. Results were consistent with the view that prolonged N2 components reflect matching of current perceptual input to memory, and thus are sensitive to experts' superior pattern recognition and memory retrieval of chunks.
