Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo

Zhou X, et al.

Nature Immunology 10, 1000-1006, (2009).

Speaker: Cheng-Yu Wang (王政育)                              Time: 15:10~16:00, Nov. 11, 2009

Commentator: Dr. Bei-Chang Yang (楊倍昌博士)      Place: Room 601

Abstract:

    Treg cells are a specialized CD4⁺ T cell lineage that is central to maintain immune system homeostasis and tolerance to self-antigens, and Foxp3 is a transcription factor playing a critical role in suppressive activity of Treg cells¹. However, Foxp3 expression is not stable and may be extinguished in regulatory T cells that convert into proinflammatory effector T cells². But the stability of Foxp3 expression on Treg in vivo is little known. In this study, the authors have developed the double-transgenic reporter experimental system (Foxp3-GFP-Cre X R26-YFP mice, the YFP is dependent on Cre-mediated excision of a loxP-flanked stop cassette) to evaluate either Foxp3 continually expressing or having ceasing at T cells in vivo. The flow cytometry analysis found that there is a population of GFP^-YFP⁺T cells existed in both the thymus and various lymphoid compartments of mice. The GFP^-YFP⁺T cells were defined as exFoxp3 cells that Foxp3 had expressed at one stage but ceased the active translation of Foxp3 protein at another stage. These exFoxp3 cells were CD25^-, with low expression of GITR and high expression of CD127, differing from the GFP⁺ YFP⁺ Treg cells. In additionally, exFoxp3 cells had a mixed phenotype,with heterogeneous expression of Treg cell markers such as FR4, CTLA-4, CD103. The exFoxp3 cells have heterogeneous CD62L expression and high CD44 expression as like as effector-memory T-cells, and they also produce IL-17, INF-γ. To investigate the relationship between instability Foxp3 and autoimmunity, they used Foxp3-GFP-Cre X R26-YFP BDC2.5 mice with autoimmune type 1 diabetes . They found the percentage of exFoxp3 cells was specifically higher in the pancreas than in nondraining inguinal lymph nodes (ILNs) and draining pancreatic lymph nodes (PLNs), the observation suggested that the autoimmune microenvironment altered T cell phenotypes. Transferring Treg cells to NOD Tcra^-/- mice showed that a portion of Treg change to exFoxp3 cells with product ofINF-γ. The transferring of exFoxp3 cells to NOD Rag2^-/- mice also induce more severe type 1 diabetes. Analysis of frequency of unique CDR3 amino acid sequences at TCR repertoire indicated that exFoxp3 cells have heterogeneous precursors, such as nTreg or conventional T cells. In summary, loss of Foxp3 in some Treg cells under autoimmune conditions may result in the conversion of former suppressor T cells into highly autoaggressive lymphocytes.

References:

1: Wan, Y.Y. et al. Regulatory T-cell functions are subverted and converted owing to attenuated Foxp3 expression. Nature 445, 766–770 (2007).

2: Zhou, L. et al. Plasticity of CD4+ T Cell Lineage Differentiation. Immunity 30, 646–655 (2009).