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

Stable Identifier
R-HSA-9942503
DOI
10.3180/R-HSA-9942503.1
Type
Pathway
Species
Homo sapiens
Compartment
nucleoplasm
ReviewStatus
5/5
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Differentiation of naive CD+ T cells to T helper 1 cells (Th1 cells)
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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).
Literature References
PubMed ID Title Journal Year
19409816 Sequential polarization and imprinting of type 1 T helper lymphocytes by interferon-gamma and interleukin-12

Schulz, EG, Mariani, L, Radbruch, A, Höfer, T

Immunity 2009
16014561 T-bet is required for optimal proinflammatory CD4+ T-cell trafficking

Lord, GM, Rao, RM, Choe, H, Sullivan, BM, Lichtman, AH, Luscinskas, FW, Glimcher, LH

Blood 2005
30846856 The evolving role of T-bet in resistance to infection

Pritchard, GH, Kedl, RM, Hunter, CA

Nat Rev Immunol 2019
17195845 Transcription factors T-bet and Runx3 cooperate to activate Ifng and silence Il4 in T helper type 1 cells

Djuretic, IM, Levanon, D, Negreanu, V, Groner, Y, Rao, A, Ansel, KM

Nat Immunol 2007
17070076 A distal conserved sequence element controls Ifng gene expression by T cells and NK cells

Hatton, RD, Harrington, LE, Luther, RJ, Wakefield, T, Janowski, KM, Oliver, JR, Lallone, RL, Murphy, KM, Weaver, CT

Immunity 2006
11397944 Role of T-bet in commitment of TH1 cells before IL-12-dependent selection

Mullen, AC, High, FA, Hutchins, AS, Lee, HW, Villarino, AV, Livingston, DM, Kung, AL, Cereb, N, Yao, TP, Yang, SY, Reiner, SL

Science 2001
12006974 T-bet is a STAT1-induced regulator of IL-12R expression in naïve CD4+ T cells

Afkarian, M, Sedy, JR, Yang, J, Jacobson, NG, Cereb, N, Yang, SY, Murphy, TL, Murphy, KM

Nat Immunol 2002
10761931 A novel transcription factor, T-bet, directs Th1 lineage commitment

Szabo, SJ, Kim, ST, Costa, GL, Zhang, X, Fathman, CG, Glimcher, LH

Cell 2000
23041064 The transcription factor T-bet is induced by multiple pathways and prevents an endogenous Th2 cell program during Th1 cell responses

Zhu, J, Jankovic, D, Oler, AJ, Wei, G, Sharma, S, Hu, G, Guo, L, Yagi, R, Yamane, H, Punkosdy, G, Feigenbaum, L, Zhao, K, Paul, WE

Immunity 2012
35381213 Differential regulation of transcription factor T-bet induction during NK cell development and T helper-1 cell differentiation

Fang, D, Cui, K, Cao, Y, Zheng, M, Kawabe, T, Hu, G, Khillan, JS, Li, D, Zhong, C, Jankovic, D, Sher, A, Zhao, K, Zhu, J

Immunity 2022
39984734 STIM1-mediated NFAT signaling synergizes with STAT1 to control T-bet expression and TH1 differentiation

Zhong, L, Wang, YH, Kahlfuss, S, Jishage, M, McDermott, M, Yang, J, Tao, AY, Hu, K, Noyer, L, Raphael, D, Patel, D, Knight, TE, Chitlur, M, Machaca, K, Feske, S

Nat Immunol 2025
24249732 Genome-wide regulatory analysis reveals that T-bet controls Th17 lineage differentiation through direct suppression of IRF4

Gökmen, MR, Dong, R, Kanhere, A, Powell, N, Perucha, E, Jackson, I, Howard, JK, Hernandez-Fuentes, M, Jenner, RG, Lord, GM

J Immunol 2013
19805038 The transcription factors T-bet and GATA-3 control alternative pathways of T-cell differentiation through a shared set of target genes

Jenner, RG, Townsend, MJ, Jackson, I, Sun, K, Bouwman, RD, Young, RA, Glimcher, LH, Lord, GM

Proc Natl Acad Sci U S A 2009
21151104 T-bet represses T(H)17 differentiation by preventing Runx1-mediated activation of the gene encoding RORγt

Lazarevic, V, Chen, X, Shim, JH, Hwang, ES, Jang, E, Bolm, AN, Oukka, M, Kuchroo, VK, Glimcher, LH

Nat Immunol 2011
20620946 Discrete roles of STAT4 and STAT6 transcription factors in tuning epigenetic modifications and transcription during T helper cell differentiation

Wei, L, Vahedi, G, Sun, HW, Watford, WT, Takatori, H, Ramos, HL, Takahashi, H, Liang, J, Gutierrez-Cruz, G, Zang, C, Peng, W, O'Shea, JJ, Kanno, Y

Immunity 2010
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T-helper 1 cell differentiation (0045063)
Authored
May, B  (2025-03-17)
Reviewed
Barbutti, I  (2025-08-04)
Lord, GM  (2025-08-05)
Created
May, B  (2025-03-17)
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