Yesterday journal Nature published very interesting study related to Foxp3+ regulatory T cells. This research revealed that "over-active" Foxo1 within Tregs specifically reduces number of peripheral tissue-resident active Tregs that control CD8 T cell-mediated tumor immunity and immunopathology.
Initially, using parabiotic mice pairs the authors showed that Tregs too undergo mixing and achieve equilibrium within 4 weeks. This indicates that Tregs are not maintained locally and require replenishment.
Next, using Foxp3-cre driven Foxo1 "active" mutant mice the authors showed that when both alleles of normal Foxo1 genes were replaced by "active" Foxo1, it led to dramatic reduction of tissue-resident Tregs (lymphoid tissue resident Tregs were less affected).
Surprisingly, when these Foxo1 homozygous mutant mice were followed for longer time (6-8 weeks), they displayed spontaneous CD8 T cell-mediated wasting disease and peripheral tissue pathologies in liver and intestine (though these tissue pathologies were different from those observed in Foxp3 mutant mice). Hemizygous Foxo1 mutant mice with only one mutant Foxo1 allele were healthy.
Interestingly, reduction of peripheral Tregs in hemizygous Foxo1 mutant mice were sufficient to confer CD8 T cell-mediated anti-tumor effect without immunopathology.
In summary, this study revealed three important results:
1. Lymphoid resident Tregs are not sufficient to control autoimmunity/immunopathology. Tissue-resident Tregs play unique and essential role in this process.
2. Level of active Foxo1 molecule control frequency of tissue-resident Tregs
3. Manipulation [reduction] of level of active Foxo1 within Tregs could improve anti-tumor immunity.
David Usharauli
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