Table 1.

IRF4 DNA binding sites and partners driving B and CD4⁺ T cell fate decisions.

DNA recognition site	Binding Partner	Relative DNA affinity	Aligned with Gene Program	Sequence Logo
EICE Ets-IRF Composite Element	PU.1 or SpiB	high	B cell GCB
AICE AP1-IRF Composite Element	BATF/JunB or BATF/cJun	high	B cell GCB / T cell Tfh
ZICE Ikaros-IRF Composite Element	Ikaros	high	B cell GCB
ISRE Interferon Stimulated Response Element	IRF4** (homodimer)	low	B cell PC / T cell Teff

^*Currently, a comprehensive understanding of each complex’s relative DNA binding efficiency is not known as only pairwise comparisons have been made. These have shown that generally, ISRE binding efficiency is substantially weaker compared to either EICE or AICE sequences[15], [16].

^**The logo for AICE2 is shown. AICE1 lacks the 4 nucleotide spacer between the AP1 and IRF sites[47]. The biological basis for AICE1 and AICE2 consensus sequences has yet to be determined. Two additional variants of AICE2 have been described (not depicted). The first is composed of a partial AP-1 motif and exhibits a greater dependency on IRF4 amounts for binding [43]. The second, which is preceded by a thymidine residue 4 nucleotides upstream from the IRF site, exhibits greater IRF4 binding than a guanine variant [47]. Together, these observations raise the possibility that variations in DNA sequence binding affinities coordinated with distinct partner interactions can drive IRF4 genome localization dynamics to control cell function and alternate cell fate decisions.

^***Heterodimerization with other IRF family members is formally possible and remains to be tested. PC: plasma cells; GCB: germinal center B cells; Teff: effector T cell; Tfh: T follicular helper cell.