The role of 2 FOXP3 isoforms in the generation of human CD4+ Tregs

• Published in: The Journal of clinical investigation 2005-11, Vol.115 (11), p.3276-3284
• Main Authors: Allan, Sarah E, Passerini, Laura, Bacchetta, Rosa, Crellin, Natasha, Dai, Minyue, Orban, Paul C, Ziegler, Steven F, Roncarolo, Maria Grazia, Levings, Megan K
• Format: Article
• Language: English
• Subjects: Cell Differentiation - genetics; Cells, Cultured; Cytokines - metabolism; Down-Regulation - genetics; Forkhead Transcription Factors - biosynthesis; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - physiology; Humans; Jurkat Cells; Lymphocyte Activation - genetics; Mutation; Protein Isoforms - biosynthesis; Protein Isoforms - genetics; Protein Isoforms - physiology; T-Lymphocyte Subsets - cytology; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; T-Lymphocytes, Regulatory - cytology; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism
• ISSN: 0021-9738
• DOI: 10.1172/jci24685

Little is known about the molecules that control the development and function of CD4+ CD25+ Tregs. Recently, it was shown that the transcription factor FOXP3 is necessary and sufficient for the generation of CD4+ CD25+ Tregs in mice. We investigated the capacity of FOXP3 to drive the generation of suppressive CD4+ CD25+ Tregs in humans. Surprisingly, although ectopic expression of FOXP3 in human CD4+ T cells resulted in induction of hyporesponsiveness and suppression of IL-2 production, it did not lead to acquisition of significant suppressor activity in vitro. Similarly, ectopic expression of FOXP3delta2, an isoform found in human CD4+ CD25+ Tregs that lacks exon 2, also failed to induce the development of suppressor T cells. Moreover, when FOXP3 and FOXP3delta2 were simultaneously overexpressed, although the expression of several Treg-associated cell surface markers was significantly increased, only a modest suppressive activity was induced. These data indicate that in humans, overexpression of FOXP3 alone or together with FOXP3delta2 is not an effective method to generate potent suppressor T cells in vitro and suggest that factors in addition to FOXP3 are required during the process of activation and/or differentiation for the development of bona fide Tregs.