Due to the large number of diseases associated to a malfunction of the hematopoietic system, there is an interest in knowing the molecular mechanisms controlling the differentiation of blood cell lineages. However, the structure and dynamical properties of the underlying regulatory network controlling this process is not well understood. This manuscript presents a regulatory network of 81 nodes, representing several types of molecules that regulate each other during the process of lymphopoiesis. The regulatory interactions were inferred mostly from published experimental data. However, 15 out of 159 regulatory interactions are predictions arising from the present study. The network is modelled as a continuous dynamical system, in the form of a set of differential equations. The dynamical behaviour of the model describes the differentiation process from the common lymphocyte precursor (CLP) to several mature B and T cell types; namely, plasma cell (PC), cytotoxic T lymphocyte (CTL), T helper 1 (Th1), Th2, Th17, and T regulatory (Treg) cells. The model qualitatively recapitulates key cellular differentiation events, being able to represent the directional and branched nature of lymphopoiesis, going from a multipotent progenitor to fully differentiated cell types. Pribil Erica epribil8@gmail.com University of Nebraska-Lincoln 2017-06-07T15:25:38Z 2017-07-25T20:40:27Z

Vitamin B9/ Folate/ Folic Acid

 2017-06-08T09:40:41Z

Interleukin-7

Gene Name: IL7

Uniprot ID: P13232

 2017-06-07T15:40:20Z

Tyrosine-protein kinase Lck

Gene Name: LCK

Uniprot ID: P06239

 2017-06-13T16:33:59Z

Fms-related tyrosine kinase 3 ligand

Gene Name: FLT3LG

Uniprot ID: P49771

 2017-06-07T16:00:28Z

Interleukin-2

Gene Name: IL2

P60568

 2017-06-07T15:38:45Z

Interleukin-18

Gene Name: IL18

Uniprot ID: Q14116

 2017-06-07T16:46:59Z

Interleukin-27 subunit alpha

Gene Name: IL27

Uniprot ID: Q8NEV9

 2017-06-07T15:44:01Z

Interleukin-12 subunit beta

Gene Name: IL12B

Uniprot ID: P29460

 2017-06-07T16:48:51Z

Homeobox protein Hox-A9

Gene Name: HOXA9

Uniprot ID: P31269

 2017-06-07T15:48:33Z

Interferon beta

Gene Name: IFNB1

Uniprot ID: P01574

 2017-06-07T15:37:27Z

B-cell Receptor

Gene Name: BCAP31

Uniprot ID: P51572

 2017-06-07T16:00:28Z

Delta-like protein 1

Gene Name: DLL1

Uniprot ID: O00548

 2017-06-07T15:51:16Z

Interleukin-21

Gene Name: IL21

Uniprot ID: Q9HBE4

 2017-06-07T15:41:44Z

Interleukin-23 subunit alpha

Gene Name: IL23A

Uniprot ID: Q9NPF7

 2017-06-07T15:42:55Z

Interferon gamma

Gene Name: IFNG

Uniprot ID: P01579

 2017-06-08T09:47:43Z

Transcription factor PU.1

Gene Name: SPI1

Uniprot ID: P17947

 2017-06-12T13:24:58Z

Transforming growth factor beta-1

Gene Name: TGFB1

Uniprot ID: P01137

 2017-06-07T16:30:56Z

Interleukin-21 receptor

Gene Name: IL21R

Uniprot ID: Q9HBE5

 2017-06-08T09:04:43Z

Protein: B-cell lymphoma/leukemia 11B

Uniprot ID: Q9C0K0

Gene Name: BCL11B

 2017-06-07T16:07:01Z

Forkhead box protein P3

Gene Name: FOXP3

Uniprot ID: Q9BZS1

 2017-06-08T10:54:00Z

Zinc finger protein 423

Gene Name: ZNF423

Uniprot ID: Q2M1K9

 2017-06-08T10:19:06Z

Nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 [Homo sapiens (human)]

UniProt ID: P19838

Gene Name: NFKB1

 2017-06-08T09:53:46Z

Interleukin-7 receptor subunit alpha

Gene Name: IL7R

Uniprot ID: P16871

 2017-06-07T16:25:45Z

Interleukin-10 receptor subunit alpha

Gene Name: IL10RA

Uniprot ID: Q13651

 2017-06-07T16:55:04Z

Signal transducer and activator of transcription 3

Gene Name: STAT3

Uniprot ID: P40763

 2017-06-08T10:00:29Z

Trans-acting T-cell-specific transcription factor GATA-3

Gene Name: GATA3

Uniprot ID: P23771

 2017-06-09T13:26:51Z

Interferon gamma receptor 2

Gene Name: IFNGR2

Uniprot ID: P38484

 2017-06-08T09:49:23Z

RAC-alpha serine/threonine-protein kinase

Uniprot ID: P31749

Gene Name: AKT1

 2017-06-07T16:36:44Z

Transcription factor 12

Gene Name: TCF12

Uniprot ID: Q99081

 2017-06-08T09:40:41Z

Zinc finger protein Helios

Gene Name: IKZF2

Uniprot ID: Q9UKS7

 2017-06-07T16:10:36Z

Zinc finger protein Gfi-1

Gene Name: GFI1

Uniprot ID: Q99684

 2017-06-09T11:05:10Z

Receptor-type tyrosine-protein kinase FLT3

Gene Name: FLT3

Uniprot ID: P36888

 2017-06-08T10:23:40Z

Signal transducer and activator of transcription 1-alpha/beta

Gene Name: STAT1

Uniprot ID: P42224

 2017-06-08T08:46:08Z

Suppressor of cytokine signaling 1

Gene Name: SOCS1

Uniprot ID: O15524

 2017-06-08T10:53:15Z

Interleukin-6 receptor subunit alpha

Gene Name: IL6R

Uniprot ID: P08887

 2017-06-11T15:25:42Z

Tumor necrosis factor

Gene Name: TNF

Uniprot ID: P01375

 2017-06-07T16:33:51Z

Uniprot ID: Q95644, Q13469, Q12968, Q14934

Nuclear factor of activated T-cells calcineurin-dependent 1-4

 2017-06-07T15:50:43Z

Interferon beta Receptor

 2017-06-08T08:38:55Z

Protein: Transcription regulator protein BACH2

Uniprot ID: Q9BYV9

Gene Name: BACH2

 2017-06-08T17:16:23Z

Interleukin-18 receptor 1

Gene Name: IL18R1

Uniprot ID: Q13478

 2017-06-07T16:48:13Z

DNA-binding protein Ikaros

Gene Name: IKZF1

Uniprot ID: Q13422

 2017-06-09T10:15:09Z

Cellular tumor antigen p53

Gene Name: TP53

Uniprot ID: P04637

 2017-06-08T10:11:34Z

Interleukin-12 receptor subunit beta-2

Gene Name: IL12RB2

Uniprot ID: Q99665

 2017-06-09T13:26:51Z

T-cell surface glycoprotein CD8 alpha chain

Gene Name: CD8

Uniprot ID: P01732

 2017-06-08T10:09:20Z

Tyrosine-protein kinase JAK3

Gene Name: JAK3

Uniprot ID: P52333

 2017-06-11T15:25:42Z

Interleukin-4 receptor subunit alpha

Gene Name: IL4R

Uniprot ID: P24394

 2017-06-08T08:49:00Z

B-cell lymphoma 6 protein

Uniprot ID: P41182

Gene Name: BCL6

 2017-06-08T17:16:23Z

Interleukin-27 receptor subunit alpha

Gene Name: IL27RA

Uniprot ID: Q6UWB1

 2017-06-08T09:36:40Z

Interleukin-2 receptor subunit alpha

Gene Name: IL2RA

Uniprot ID: P01589

 2017-06-08T08:43:52Z

Interleukin-17A

Gene Name: IL17A

Uniprot ID: Q16552

 2017-06-07T16:27:22Z

Apoptosis regulator

Uniprot ID: P10415

Gene Name: BCL2

 2017-06-08T08:58:24Z

PR domain zinc finger protein 1

Uniprot ID: O75626

Gene Name: PRDM1

 2017-06-08T10:19:06Z

Runt-related transcription factor 1

Gene Name: RUNX1

Uniprot ID: Q01196

 2017-06-09T15:19:57Z

Zinc finger and BTB domain-containing protein 7B

Gene Name: ZBTB7B

Uniprot ID: O15156

 2017-06-08T10:56:08Z

Eomesodermin homolog

Gene Name: EOMES

Uniprot ID: O95936

 2017-06-08T09:59:40Z

Immunoglobulin kappa variable 3-20

Gene Name: IGKV3-20

Uniprot ID: P01619

 2017-06-08T08:58:24Z

TGF-beta receptor type-1

Gene Name: TGFBR1

Uniprot ID: P36897

 2017-06-07T16:36:44Z

Interleukin-4

Gene Name: IL4

Uniprot ID: P05112

 2017-06-08T08:48:09Z

Interleukin-1 receptor-associated kinase 1

Gene Name: IRAK1

Uniprot ID: P51617

 2017-06-08T09:46:45Z

Mothers against decapentaplegic homolog 3

Gene Name: SMAD3

Uniprot ID: P84022

 2017-06-08T09:04:43Z

Transcription factor 7

Gene Name: TCF7

Uniprot ID: P36402

 2017-06-08T09:40:41Z

Paired box protein Pax-5

Gene Name: PAX5

Uniprot ID: Q02548

 2017-06-08T10:20:07Z

Mothers against decapentaplegic homolog 2

Gene Name: SMAD2

Uniprot ID: Q15796

 2017-06-08T10:00:29Z

Signal transducer and activator of transcription 6

Gene Name: STAT6

Uniprot ID: P42226

 2017-06-08T09:40:41Z

Tumor necrosis factor receptor superfamily member 1B

Gene Name: TNFRSF1B

Uniprot ID: P20333

 2017-06-07T16:34:41Z

Mitogen-activated protein kinase 1

Gene Name: MAPK1

Uniprot ID: P28482

 2017-06-08T10:23:40Z

Perforin-1

Gene Name: PRF1

Uniprot ID: P14222

 2017-06-08T09:59:40Z

Neurogenic locus notch homolog protein 1

Gene Name: Notch1

Uniprot ID: P46531

 2017-06-11T15:25:42Z

T-box transcription factor TBX21

Gene Name: TBX21

Uniprot ID: Q9UL17

 2017-06-08T10:09:20Z

Interleukin-10

Gene Name: IL10

Uniprot ID: P22301

 2017-06-07T16:55:04Z

Interferon regulatory factor 4

Gene Name: IRF4

Uniprot ID: Q15306

 2017-06-12T13:24:58Z

Signal transducer and activator of transcription 5A

Gene Name: STAT5A

Uniprot ID: P42229

 2017-06-08T10:06:29Z

Interleukin-23 receptor

Gene Name: IL23R

Uniprot ID: Q5VWK5

 2017-06-07T16:52:26Z

T-cell surface glycoprotein CD4

Gene Name: CD4

Uniprot ID: P01730

 2017-06-08T10:09:20Z

Tyrosine-protein kinase JAK1

Gene Name: JAK1

Uniprot ID: P23458

 2017-06-08T09:49:23Z

Granzyme B

Gene Name: GZMB

Uniprot ID: P10144

 2017-06-08T09:43:13Z

Nuclear receptor ROR-gamma

Gene Name: RORC

Uniprot ID: P51449

 2017-06-08T10:54:00Z

Signal transducer and activator of transcription 4

Gene Name: STAT4

Uniprot ID: Q14765

 2017-06-09T13:26:51Z

Interleukin-6

Gene Name: IL6

Uniprot ID: P05231

 2017-06-07T16:27:22Z

B-lymphocyte antigen CD19

Uniprot ID: P15391

Gene Name: CD19

 2017-06-07T16:07:11Z

X-box-binding protein 1

Gene Name: XBP1

Uniprot ID: P17861

 2017-06-08T10:12:21Z

EOMES, IRAK, STAT4 and Tbet activate IFNg unless STAT3.

IFNg activity is halted when IRAK is absent.

Increased STAT4 activity is associated with increased IFNg activity.

Increased STAT3 activity is associated with decreased IFNg activity.

EOMES activity is associated with increased IFNg activity.

Increased Tbet activity is associated with increased IFNg activity.

 S_50 1 S_12 1 S_78 1 S_12 1 S_68 1 S_12 1 S_55 1 S_12 1

Irf4 activates PU1. Gfi1 or Ikaros inhibit PU1.

Irf4 activation encodes PU1.

Gfi1 inhibits PU1 by preventing binding.

It is predicted that Ikaros inhibits PU1 to represent the maintenance of the intermediates of Ikaros and PU1 needed for developing lymphocyte lineages.

 S_70 1

Foxp3 activates TGFb.

It is predicted that Foxp3 activates TGFb in order to account for the induction of TGFb in Foxp3-Treg cells.

 S_7 1

IL21 activates IL21R.

IL21 activates IL21R through binding.

 S_64 1

Notch1 and TCF1 activate Bcl11b.

Notch1 activates Bcl11b through binding.

TCF1 activates Bcl11b through binding.

 S_67 1 S_57 1

Foxp3, SMAD2 or SMAD3 activate Foxp3 unless GATA3, RORgt, STAT3 and Tbet are active.

Increased GATA3 activity is associated with decreased Foxp3 activity.

Increased RORgt activity is associated with decreased Foxp3 activity.

SMAD3 activates Foxp3 through binding.

Foxp3 regulates itself through an unknown mechanism.

Increased SMAD2 activity is associated with increased Foxp3 activity.

STAT3 inhibits Foxp3 through binding to an enhancer site.

Tbet inhibits Foxp3 through a mutually inhibitory circuit.

 S_7 1 S_13 1 S_77 1 S_12 1 S_68 1 S_59 1 S_13 1 S_77 1 S_12 1 S_68 1 S_56 1 S_13 1 S_77 1 S_12 1 S_68 1

Runx1 active Ebf1 unless Runx3 is active.

It is predicted that Runx3 inhibits Ebf1 to simulate Ebf1 downregulation in the CD8 lineage.

Runx1 activates Ebf1 through binding.

 S_48 1 S_36 1

BCR activates NFkB.

BCR activates NFkB by promoting the translocation of the transcription factor, NFkB.

 S_60 1

IL7 activates IL7R unless TCR is active.

IL7 activates IL7R through binding.

TCR induction reduces IL7R activity.

 S_22 1 S_23 1

IL10 activates IL10R.

IL10 activates IL10R through binding.

 S_69 1

IL10R, IL21R, IL23R or JAK3 activate STAT3.

Increased JAK3 activity is associated with increased JAK3 activity.

IL10R activates STAT3 through phosphorylation.

IL23R activates STAT3 by directly associating with the STAT3 signal transducer.

Increased IL21R activity is associated with increased STAT3 activity.

 S_5 1 S_72 1 S_39 1 S_11 1

GATA3, STAT6 and TCF1 activate GATA3, unless Foxp3, HEB, RORgt, Runx1 and Tbet are active.

GATA3 activates itself by directly binding to the promoter.

HEB inhibits GATA3 activity and encourages T-cell specification.

Increased RORgt activity is associated with decreased GATA3 activity.

Increased STAT6 activity is associated with activation of GATA3.

TCF1 activates GATA3 through binding.

GATA3 is inhibited by Foxp3 through an unknown mechanism.

Increased Runx1 activity is associated with decreased GATA3 activity.

Tbet inhibits GATA3 through a mutually inhibitory circuit.

 S_57 1 S_16 1 S_77 1 S_7 1 S_48 1 S_68 1 S_13 1 S_16 1 S_77 1 S_7 1 S_48 1 S_68 1 S_62 1 S_16 1 S_77 1 S_7 1 S_48 1 S_68 1

IFNg activates IFNgR.

IFNg activates IFNgR through binding.

 S_1 1

AKT is activated by TNFR2.

TNFR2 activates AKT via phosphorylation.

 S_63 1

Notch1 activates HEB.

Increased Notch1 activity is associated with increased HEB activity.

 S_67 1

NFkB activates Helios.

Increased NFkB activity is associated with increased Helios activity.

 S_9 1

Ikaros activates Gfi1.

Ikaros activates Gfi1 through binding to the promoter.

 S_33 1

Flt3L or Hoxa9 activate Flt3 unless Pax5 is active.

Hoxa9 activates Flt3 through binding.

Increased Pax5 activity is associated with decreased Flt3 activity.

Flt3L activates Flt3 through binding.

 S_27 1 S_58 1 S_44 1 S_58 1

IFNbR, IL27R or JAK1 activate STAT1.

JAK1 activates STAT1 through phosphorylation.

IL27R activates STAT1 through phosphorylation.

IFNbR activates STAT1 through phosphorylation.

 S_74 1 S_42 1 S_28 1

STAT1 or Tbet activate SOCS1.

STAT1 activates SOCS1 via binding.

Increased Tbet activity is associated with increased SOCS1 activity.

 S_68 1 S_20 1

IL6 activates IL6R.

IL6R recognizes IL6, which activates it.

 S_79 1

RORgt activates TNFa.

It is predicted that RORgt activates TNFa to account for the regulation of TNFa production by Th17 cells.

 S_77 1

TCR activates NFAT.

TCR activates NFAT via dephosphorylation.

 S_23 1

IFNb activates IFNbR.

IFNb activates IFNbR through binding.

 S_52 1

Bcl6 or Pax5 activates Bach2.

By regulating chromatin accessibility to the Bach2 promoter, Pax5 activates Bach2.

Bcl6 activates Bach2 through binding.

 S_41 1 S_58 1

IL18 activates IL18R unless STAT6 is active.

STAT6 inhibits IL18R by downregulating a subunit of the IL-18 receptor.

IL18 activates IL18R through binding.

 S_32 1 S_62 1

PU1 activates Ikaros.

It is predicted that PU1 activates Ikaros to represent the maintenance of the intermediates of Ikaros and PU1 needed for developing lymphocyte lineages.

 S_3 1

CD8 activates Runx3, unless CD4, STAT5 and ThPOK are active.

STAT5 and CD8 activate Runx3.

Increased ThPOK activity is associated with decreased Runx3 activity.

STAT5 activates Runx3 via induction.

CD4 activity inhibits Runx3 activity.

CD8 actiivty increases Runx3 activity.

 S_38 1 S_49 1 S_71 1 S_73 1 S_71 1 S_38 1

IL12 activates IL12R unless STAT6 is active.

IL12R is activated by IL12 by recognizing it.

STAT6 inhibits IL12R activity, by inhibiting one unit of the IL12 receptor.

 S_35 1 S_62 1

CD8, Notch1 or Runx3 active CD8 unless Ebf1, TCR and ThPOK are active.

When ThPOK is activated CD8 activity is inhibited.

Notch1 activity is associated with increased CD8 activity.

It is predicted that Ebf1 inhibits CD8 activity to account for the CD8 T-cells being inhibted in the B cell lineage

Increased Runx3 activity is associated with increased CD8 activity.

Increased TCR signalling is associated with downregulation of CD8.

CD8 regulates itself through epigenetic expression.

 S_38 1 S_49 1 S_8 1 S_23 1 S_36 1 S_49 1 S_8 1 S_23 1 S_67 1 S_49 1 S_8 1 S_23 1

IL6R or IL7R activate JAK3, unless Notch1 is active.

Notch1 activity encourages the ubiquitin mediated breakdown of JAK3.

IL6R activates JAK3 through signaling.

IL7R activates JAK3 through phosphorylation.

 S_10 1 S_67 1 S_24 1 S_67 1

IL4 activates IL4R unless SOCS1 is active.

IL4 activates IL4R by binding.

SOCS1 inhibits IL4R by inhibiting compotents of the pathway.

 S_54 1 S_21 1

IL21R and Ebf1 activate Bcl5 unless Blimp1 and Irf4 are active.

Ebf1 activates Bcl6 through binding.

Blimp1 activates Bcl6 through binding.

Irf4 inhibits Bcl6 through binding.

IL21R activates Bcl6 via JunD/AP-1 activation.

 S_5 1 S_8 1 S_47 1 S_70 1

IL27 activates IL27R.

IL27 activates IL27R through binding.

 S_34 1

IL2 activates IL2R.

IL2 actives IL2R through binding.

 S_29 1

RORgt activates IL17.

RORgt activates IL17 by inducing transcription.

 S_77 1

FR4 or STAT5 activate Bcl2.

Increased FR4 activity is associated with increased Bcl2 activity.

STAT5 mediated by IL7 singaling activates Bcl2.

 S_71 1 S_51 1

Blimp1 is activated by Irf4 unless Bach2, Bcl6 and Pax5 are active.

Pax5 inhibits Blimp1 through binding.

Bach2 inhibits Blimp1 through binding to a Maf recognition element of the Prdm1 gene, which codes for Blimp1.

Irf4 activates Blimp1 through binding.

Bcl6 binds directly to the Prdm1 gene, preventing Blimp1 expression.

 S_70 1 S_58 1 S_30 1 S_41 1

Runx1 activates Runx1, unless Notch1, Runx3, TCR and ThPOK are active.

It is predicted that Notch1 inhibits Runx1 to account for the downregulation of Runx1 in T cell development.

It is predicted that ThPOK inhibits Runx1 to account for Runx1 downregulation in the early stages of T cell development.

Increased Runx3 activity is associated with decreased Runx1 activity.

It is predicted that Runx1 activates itself to account for the constant activation in lymphopoiesis.

TCR inhibits Runx1 via inhibiting a promoter.

 S_48 1 S_67 1 S_49 1 S_36 1 S_23 1

Foxp3, GATA3, RORgt, TCR or ThPOK activate ThPOK.

CD4 activates ThPOK, unless CD8 is active.

Tbet activates ThPOK, unless Runx3 is active.

GATA3 activates ThPOK through binding.

ThPOK activates itself by prohibiting inhibitory factor from binding.

Increased RORgt activity is associated with increased ThPOK activity.

Runx3 inhibits ThPOK by binding to a silencing portion of the gene.

Foxp3 activates ThPOK to account for positive regulations of factors in CD4+ cells.

TCR activates ThPOK through an unknown mechanism.

Increased CD4 activity increases ThPOK activity.

It is predicted that CD8 inhibits ThPOK activity to account for the decision between CD4 and CD8 cells.

It is proposed that Tbet activates ThPOK to account for master regulators in the CD4 lineage.

 S_49 1 S_68 1 S_36 1 S_23 1 S_13 1 S_77 1 S_7 1 S_73 1 S_38 1

IL27R or Tbet activate EOMES when Runx3 is also active.

Runx3 activity is required for EOMES induction.

Increased IL27R activity is associated with increased EOMES activity, possibly in a mechanisn involving STAT1.

Through an IL27 independent mechanism, Tbet activates EOMES.

 S_42 1 S_36 1 S_68 1 S_36 1

Foxp3 and B9 activate FR4.

Increased Foxp3 activity is associated with increased FR4 activity.

B9 activates the folate receptor.

 S_7 1 S_2 1

TGFb activates TGFbR.

TGFb activates TGFbR through binding.

 S_4 1

GATA3 activates IL4 unless STAT1 is active.

Increased GATA3 activity is associated with increased IL4 activity.

STAT1 inhibits IL4 by forming a complex with other proteins.

 S_13 1 S_20 1

IL18R activates IRAK.

Increased IL18R activity is associated with increased IRAK activity.

 S_31 1

TGFbR activates SMAD3, unless AKT is active.

TGFbR activates SMAD3 by promoting translocation in the nucleus.

AKT inhibits SMAD3 by preventing phosphorylation.

 S_53 1 S_15 1

Notch1 activates TCF1.

Increased Notch1 activity is associated with increased TCF1 activity.

 S_67 1

Ebf1 activates Pax5, unless Blimp1, Flt3, Irf4 and ThPOK are active.

STAT5 along with Ebf1 activates Pax5, unless Blimp1, Irf4 and ThPOK are active.

It is predicted that ThPOK inhibits Pax5 to account for B cell program inhibition in the CD4 lineage.

Blimp1 inhibits Pax5 by binding.

Ebf1 activates Pax5 through binding.

Increased STAT5 activity is associated increased Pax5 activity.

Irf4 activates Pax5 through binding.

It is predicted that Flt3 inhibits Pax5 to account for the inhibition of the B cell program in CLP cells.

 S_71 1 S_49 1 S_47 1 S_70 1 S_8 1 S_8 1 S_49 1 S_47 1 S_70 1 S_19 1

TGFbR activates SMAD2.

By promoting translocation in the nucleus, TGFbR activates SMAD2.

 S_53 1

IL4R activates STAT6.

IL4R activates STAT6 by encouraging transcription.

 S_40 1

TNFa activates TNFR2.

TNFa activates TNFR2 through binding.

 S_25 1

BCR or Flt3 activate ERK.

BCR phosphorylatie ERK, causing activation.

Flt3 activates ERK through phosphorylation.

 S_60 1 S_19 1

EOMES activates Prf1.

EOMES regulates Prf1 through binding.

 S_50 1

Dll1 activates Notch1.

Dll1 acts as a ligand for Notch1, activating it.

 S_61 1

STAT1 or Tbet activates Tbet, unless Foxp3, GATA3 and RORgt are active.

GATA3 inhibits Tbet through an unknown mechanism.

Increased STAT1 activity is associated with increased Tbet activity.

Increased RORgt activity is associated with decreased Tbet activity.

When Foxp3 was absent, Tbet was active.

Tbet activates itself through an unknown mechanism.

 S_68 1 S_13 1 S_77 1 S_7 1 S_20 1 S_13 1 S_77 1 S_7 1

GATA3 activates IL10.

Increased GATA3 activity is associated with increased IL10 activity.

 S_13 1

Blimp1 or NFkB activate Irf4 along with Ebf1, unless Flt3 is active.

It is predicted that Ebf1 activates Irf4 to represent mechanisms that control the B cell lineage.

Blimp1 activates Irf4 by inducing the expression of the gene creating a positive feedback loop.

It is predicted that Flt3 inhibits Irf4 to represent inhibition of the PC program in CLP cells.

NFkB activates Irf4 through binding.

 S_9 1 S_19 1 S_8 1 S_47 1 S_19 1 S_8 1

IL2R or JAK3 activate STAT5, unless SOCS1 is active.

IL2R activates STAT5 by encouraging its transcription.

Increased JAK3 activity is associated with increased STAT5 activity.

SOCS1 inhibits STAT5 by preventing its phosphorylation.

 S_43 1 S_21 1 S_39 1 S_21 1

IL23 activates IL23R.

IL23 activates IL23R through binding.

 S_75 1

CD4, Notch 1 or ThPOK active CD4 unless Ebf1 and Runx3 are both active.

Increased Notch1 activity is associated with increased CD4 activity.

ThPOK activates CD4 through an unknown mechanism.

It is predicted that Ebf1 inhibits CD4 activity to account for the CD8 T-cells being inhibted in the B cell lineage.

Runx3 inhibits CD4 by binding.

CD4 regulates itself through epigenetic expression.

 S_67 1 S_8 1 S_36 1 S_49 1 S_8 1 S_36 1 S_73 1 S_8 1 S_36 1

IFNgR activates JAK1.

IFNgR activates JAK1 through binding and phosphorylation.

 S_14 1

EOMES activates Gzmb.

EOMES regulates Gzmb through binding.

 S_50 1

RORgt activates RORgt, unless Foxp3, GATA3 and Tbet are active.

SMAD2 and STAT3 activate RORgt.

Increased GATA3 is associated with decreased RORgt activity.

RORgt activates itself through positive self regulation.

Through interacting directly with the transcription factor, RORgt behavior is inhibited.

SMAD2 activates RORgt through acting as a cactivator.

Increased STAT3 activity is associated with increased RORgt activity.

Tbet inhibits RORgt via a mutual inhibitory circuit.

 S_59 1 S_12 1 S_77 1 S_13 1 S_7 1 S_68 1

IL12R activates STAT4, unless GATA3 is active.

Increased GATA3 activity is associated with decreased STAT4 activity.

Increased IL12R activity encourages STAT4 transcription.

 S_37 1 S_13 1

RORgt activates IL6.

Increased RORgt activity encourages IL6 production.

 S_77 1

Pax5 activates CD19.

Pax5 activates CD19 through binding.

 S_58 1

Blimp1 activates XBP1.

XBP1 expression is dependent on the activity of Blimp1.

 S_47 1