Duel(ling) precursors in thymic Treg development

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Science Immunology  07 Jun 2019:
Vol. 4, Issue 36, eaax9509
DOI: 10.1126/sciimmunol.aax9509


Functional thymus derived regulatory T cells can be generated by two distinct pathways.

Regulatory T cells (Treg) are critical in maintaining immune homeostasis and express the transcription factor Foxp3. While it has been clear for some time that a substantial percentage of CD4+CD25hiFoxp3+ Tregs are derived in the thymus, a description of early Treg precursors and their subsequent pathways of maturation have been more controversial. Two distinct precursors have been described that differ in their expression of FoxP3 and the high affinity IL2 receptor alpha chain (CD25). Owen et al. used single-cell gene expression analysis and an impressive array of genetically modified mouse strains to address whether CD4+CD25+Foxp3 (termed CD25+TregP) and CD4+CD25Foxp3lo (termed Foxp3loTregP) cells are both bona fide Treg precursors, whether they represent distinct lineages with different developmental requirements and whether the resulting Tregs have differential function capacity.

The authors show that CD25+TregP and Foxp3loTregP precursor populations have distinct αβTCR repertoires and can both develop into functional mature Tregs. The authors show that TCRs expressed by CD25+TregP are higher affinity for self-antigen based on a nur77GFP reporter. The two Treg precursor populations also have distinct gene expression profiles. Furthermore, CD28 costimulation and canonical NFκB signals are substantially more important for CD25+TregP compared with Foxp3loTregP. Most interestingly, the Tregs derived from CD25+TregP have the capacity to suppress experimental autoimmune encephalomyelitis while Foxp3loTregP derived cells cannot. Are both of these pathways required for “normal” immune homeostasis? Is the only difference in mature Tregs arising from these distinct pathways the TCR repertoire, or are distinct gene expression signatures maintained, resulting in alternate underlying mechanism of regulation? Whether distinct precursor populations and resultant functionally disparate populations of CD4+CD25+Foxp3+ Tregs exist in humans and other questions relevant to generation of Tregs for adoptive therapy remain to be answered.

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