Differentiation of naive CD4+ T cells to T helper 1 cells (Th1 cells)

TBX21 with RUNX3 then enhances expression of IFNG (inferred from mouse homologs in Szabo et al. 2000, Mullen et al. 2001, Hatton et al. 2006, Djuretic et al. 2007, Jenner et al. 2009, Zhu et al. 2012), thereby creating a positive feedback loop that maintains TBX21 expression. TBX21 also binds the transcription factor RUNX1 and prevents RUNX1 from activating expression of RORC, an activator of Th17 differentiation (inferred from mouse homologs in Lazarevic et al. 2011). TBX21 also represses expression of IL4, an activator of Th2 differentiation (Jenner et al. 2009, and inferred from mouse homologs in Zhu et al. 2012). Thus, TBX21 restricts naive CD4+ T cells to the Th1 fate.

TBX21 then directly activates expression of Th1 regulators and cell markers, including C-X-C chemokine receptor type 3 (CXCR3) (inferred from mouse homologs in Szabo et al. 2000, Lord et al. 2005, Zhu et al. 2012, Gökmen et al. 2013), Tumor necrosis factor (TNF, TNFA) (Jenner et al. 2009, and inferred from mouse homologs in Zhu et al. 2012), C-C motif chemokine 3 (CCL3) (Jenner et al. 2009, and inferred from mouse homologs in supplement-02 of Zhu et al. 2012). TBX21 also upregulates expression of Protein‑tyrosine sulfotransferase 2 (TPST2) (inferred from mouse homologs in Lord et al. 2005), which is linked to the ability of Th1 cells to migrate and access inflamed skin.