Long-lived plasma cells

Long-lived plasma cells are memory B cells that secrete high-affinity antibodies and help preserve immunological memory to specific antigens.^[11] IRF4 plays a significant role at multiple stages of long-lived plasma cell differentiation. The effects of IRF4 expression are heavily dependent on the quantity of IRF4 present.^[10] A limited presence of IRF4 activates BCL6, which is essential for the formation of germinal centers, from which plasma cells differentiate.^[11] In contrast, elevated expression of IRF4 represses BCL6 expression and upregulates Blimp-1 and Zbtb20 expression.^[11] This response, dependent on a high dose of IRF4, helps initiate the differentiation of germinal center B cells into plasma cells.^[11]

IRF4 expression is necessary for isotype class switch recombination in germinal center B cells that will become plasma cells. B cells that lack IRF4 fail to undergo immunoglobulin class switching.^[9] Without IRF4, B cells fail to upregulate the AID enzyme, a component necessary for inducing mutations in immunoglobulin switch regions of B cell DNA during somatic hypermutation.^[9] In the absence of IRF4, B cells will not differentiate into Ig-secreting plasma cells.^[9]

IRF4 expression continues to be necessary for long-lived plasma cells once differentiation has occurred. In the absence of IRF4, long-lived plasma cells disappear, suggesting that IRF4 plays a role in regulating molecules essential for the continued survival of these cells.^[11]

Dendritic cells (DCs)

The transcription factors IRF4 and IRF8 work in concert to achieve DC differentiation.^[8][9] IRF4 expression is responsible for inducing development of CD4+ DCs, while IRF8 expression is necessary for the development of CD8+ DCs.^[9] Expression of either IRF4 or IRF8 can result in CD4-/CD8- DCs.^[9] Differentiation of DC subtypes also depends on IRF4's interaction with the growth factor GM-CSF.^[8] IRF4 expression is necessary for ensuring that monocyte-derived dendritic cells (Mo-DCs) can cross-present antigen to CD8+ cells.^[8]

Macrophages

IRF4 and IRF8 are also significant transcription factors in the differentiation of common myeloid progenitors (CMPs) into macrophages.^[8] IRF4 is expressed at a lower level than IRF8 in these progenitor cells; however, IRF4 expression appears to be particularly important for the development of M2 macrophages.^[8] JMJD3, which regulates IRF4, has been identified as an important regulator of M2 macrophage polarization, suggesting that IRF4 may also take part in this regulatory process.^[8]