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

Summary

Organism

Homo sapiens (human)

Reactome

R-HSA-9942503

PubChem

R-HSA-9942503

Description

A conjunction of signaling from the T cell receptor, Interferon gamma (IFNG), and Interleukin-12 (IL12) induces the differentiation of T helper 1 cells (Th1) by activating the master regulator TBX21 (T-bet). Expression of TBX21 (T-bet) occurs in two phases. The first phase is dependent on IFNG acting via STAT1 and the T cell receptor acting via calcium, calcineurin, and NFATC1 (inferred from mouse homologs in Zhong et al. 2025). During the first phase, TBX21 activates expression of IL21RB2, a subunit of the receptor for IL12 (inferred from mouse homologs in Mullen et al. 2001, Afkarian et al. 2002, Schulz et al. 2009, Zhu et al. 2012). The second phase is dependent on IL12 acting via IL21RB2 and STAT4 (Inferred from mouse cells in Schulz et al. 2009, Wei et al. 2010, Zhu et al. 2012, Fang et al. 2022).
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 (Pritchard et al. 2019).

Click on a node on the pathway to see its details. Glycoproteins are marked with a glycoprotein icon in their name.

SPV: a JavaScript Signaling Pathway Visualizer, Bioinformatics, 2018

Displaying **all 8** entries
UniProt ID	Protein Name	Gene Symbol	Pathway Viewer
O60704	Protein-tyrosine sulfotransferase 2	TPST2	view
O95644	Nuclear factor of activated T-cells, cytoplasmic 1	NFAT2 NFATC NFATC1	view
P01375	Tumor necrosis factor	TNF TNFA TNFSF2	view
P01579	Interferon gamma	IFNG	view
Q01196	Runt-related transcription factor 1	AML1 CBFA2 RUNX1	view
Q13761	Runt-related transcription factor 3	AML2 CBFA3 PEBP2A3 RUNX3	view
Q14765	Signal transducer and activator of transcription 4	STAT4	view
Q99665	Interleukin-12 receptor subunit beta-2	IL12RB2	view

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