Transcription Factor Networks Directing the Development, Function, and Evolution of Innate Lymphoid Effectors

Abstract

Mammalian lymphoid immunity is mediated by fast and slow responders to pathogens. Fast innate lymphocytes are active within hours after infections in mucosal tissues. Slow adaptive lymphocytes are conventional T and B cells with clonal antigen receptors that function days after pathogen exposure. A transcription factor (TF) regulatory network guiding early T cell development is at the core of effector function diversification in all innate lymphocytes, and the kinetics of immune responses is set by developmental programming. Operational units within the innate lymphoid system are not classified by the types of pathogen-sensing machineries but rather by discrete effector functions programmed by regulatory TF networks. Based on the evolutionary history of TFs of the regulatory networks, fast effectors likely arose earlier in the evolution of animals to fortify body barriers, and in mammals they often develop in fetal ontogeny prior to the establishment of fully competent adaptive immunity.

Id proteins suppress E2A-driven innate-like T cell development prior to TCR selection

“…This included genes 241 such as Tcf7, Bcl11b, Sox4 and Gzma. [22,25,45] While direct regulation of PLZF (encoded by 242 Zbtb16) by E2A has been reported previously, [46] we found E2A binding to intragenic, rather …”

“…[45,67] Hence, we propose that innate- 5. Kreslavsky T., Savage A. K., Hobbs R., Gounari F., Bronson R., Pereira P., Pandolfi P. P., 9.…”

A cold-blooded view of adaptive immunity

“…It is fitting that studies of their evolution should be a new priority, considering that it is tempting to propose that ILCs (especially) may have predated lymphocytes bearing antigen receptors 181,182 .…”

“…Generally, ILCs have not yet been examined in any detail in species other than humans and rodents. Lamprey lymphocytes have been detected that bear no antigen receptors, and these are candidates for NK cells and other ILCs 181 .…”

Developmental Acquisition of Regulomes Underlies Innate Lymphoid Cell Functionality

“…Like T and B lymphocytes, ILCs are derived from common lymphoid progenitors (CLPs), and further specified by an array of transcription factors (TFs) (De Obaldia and Bhandoola, 2015; Kang and Malhotra, 2015; Klose and Diefenbach, 2014). The transcriptional regulator inhibitor of DNA binding 2, Id2, for instance, counteracts the effects of E proteins to limit the development of T and B lymphocytes.…”