Journal
JOURNAL OF IMMUNOLOGY
Volume 186, Issue 12, Pages 6788-6797Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1100269
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Funding
- Canadian Institutes for Health Research New Emerging Team in Clinical Autoimmunity: Immune Regulation and Biomarker Development in Pediatric and Adult Onset Autoimmune Diseases [CIHR MOP 84041]
- Juvenile Diabetes Research Foundation [1-2008-968]
- Canadian Institutes for Health Research
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Natural FOXP3(+)CD4(+)CD25(High) regulatory T cells are critical in immunological self-tolerance. Their characterization in humans is hindered by the failure to discriminate these cells from activated effector T cells in inflammation. To explore the relationship between FOXP3 expression and regulatory function at the clonal level, we used a single-cell cloning strategy of CD25-expressing CD4(+) T cell subsets from healthy human donors. Our approach unveils a functional heterogeneity nested within CD4(+)CD25(High)FOXP3(+) T cells, and typically not revealed by conventional bulk assays. Whereas most cells display the canonical regulatory T (T-REG) cell characteristics, a significant proportion of FOXP3(+) T cells is compromised in its suppressive function, despite the maintenance of other phenotypic and functional regulatory T hallmark features. In addition, these nonsuppressive FOXP3(+) T cells preferentially emerge from the CD45RO(+) memory pool, and arise as a consequence of a rapid downregulation of FOXP3 expression upon T cell reactivation. Surprisingly, these dysfunctional T-REG cells with unstable FOXP3 expression do not manifest overt plasticity in terms of inflammatory cytokine secretion. These results open a path to an extensive study of the functional heterogeneity of CD4(+)CD25(High)FOXP3(+) T-REG cells and warrant caution in the sole use of FOXP3 as a clinical marker for monitoring of immune regulation in humans. The Journal of Immunology, 2011, 186: 6788-6797.
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