Defining Human Regulatory T Cells beyond FOXP3: The Need to Combine Phenotype with Function
Abstract
1. Introduction
2. Revisiting Human Treg Phenotypes
2.1. FOXP3 Is Neither Specific nor Exclusive to Human Tregs
2.2. The Complexity of the Treg Universe, as Revealed by Their Phenotypes
Markers | ‘Treg-Specific’ [Reference] | Also Expressed in Teff Cells [Reference] |
---|---|---|
4-1BB/CD137 | [71] | [72] |
CD25 | [8] | [46,73] |
FOXP3 | [74,75,76] | [45,46,47] |
GARP | [77] | [78,79] |
GITR | [9,80] | [81] |
GPA33 | [82] | [61] |
Helios | [54,83,84,85] | [53] |
Lag-3 | [86,87] | [88] |
LAP | [10] | [79] |
Neuropilin | [11,56] | [55] |
OX40 | [71] | [89] |
TNFR2/CD120b | [90] | [91] |
2.3. Does the Priming Site Determine the Treg Type?
3. Lessons from Treg Clones
4. Functional Diversity of Tregs
4.1. Interaction with Antigen-Presenting Cells
4.2. Inhibitory Cytokines
4.3. Metabolic Disruption
4.4. Direct Interaction with Effector T Cells
4.5. Induction of Apoptosis
4.6. Evolving Understanding of a Regulatory Role in HLA-DR Expression and Extracellular Vesicles
5. A New View on the Treg Universe
Author Contributions
Funding
Conflicts of Interest
Abbreviations
APCs | Antigen-presenting cells |
CTLA4 | Cytotoxic T-lymphocyte-associated protein 4 |
DR | Death receptor |
EVs | Extracellular vesicles |
Gal | Galectin |
GITR | Glucocorticoid-induced TNFR-related protein |
GPA33 | Glycoprotein A33 |
GzmB | Granzyme B |
IDO | Indoleamine 2,3 dioxygenase |
IPEX | Immune dysfunction/polyendocrinopathy/enteropathy/X-linked |
iTregs | Tregs induced in vitro |
Lag-3 | Lymphocyte-activation gene 3 |
LAP | Latency-associated peptide |
MAGE-A3 | Melanoma antigen family A3 |
mDCs | Inflammatory monocyte-derived dendritic cell |
Nrp-1 | Neuropilin |
nTregs | Naturally occurring Tregs |
PD-1 | Programmed cell death protein |
PD-L1 | Programmed death-ligand 1 |
PFN | Perforin |
pTregs | Tregs generated in the peripheral tissues |
TCR | T cell receptor |
Teff | Effector T cells |
TIGIT | T cell immunoreceptor with immunoglobulin and ITIM domain |
TIM3 | T cell immunoglobulin and mucin domain 3 |
tolDCs | Tolerogenic dendritic cells |
Tr1 | Type 1 regulatory T cells |
Tr2 | Type 2 regulatory T cells |
TRAIL | Tumor necrosis factor-related apoptosis-inducing ligand |
Tregs | Regulatory T cells |
TSDR | Treg-specific demethylated region |
tTregs | Tregs generated in the thymus |
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Cluster 1 | Cluster 2 | Cluster 3 | |
---|---|---|---|
Mechanism of priming | iTregs primed by tolDCs | iTregs primed by tolDCs | iTregs primed by tolDCs |
Function | Monocyte killing Inhibition of naïve T cells and Th1 responses | Monocyte killing | Monocyte killing Strong inhibition of naïve T cells and Th1 responses |
Expression of markers | High amounts of IL-10, TNF, IFN-γ, and IL-13 CTLA4 Granzyme B | Granzyme B | CTLA4 Some make IL-10 |
Peculiarity | Reversed TCR docking | Infectious tolerance |
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Gootjes, C.; Zwaginga, J.J.; Roep, B.O.; Nikolic, T. Defining Human Regulatory T Cells beyond FOXP3: The Need to Combine Phenotype with Function. Cells 2024, 13, 941. https://doi.org/10.3390/cells13110941
Gootjes C, Zwaginga JJ, Roep BO, Nikolic T. Defining Human Regulatory T Cells beyond FOXP3: The Need to Combine Phenotype with Function. Cells. 2024; 13(11):941. https://doi.org/10.3390/cells13110941
Chicago/Turabian StyleGootjes, Chelsea, Jaap Jan Zwaginga, Bart O. Roep, and Tatjana Nikolic. 2024. "Defining Human Regulatory T Cells beyond FOXP3: The Need to Combine Phenotype with Function" Cells 13, no. 11: 941. https://doi.org/10.3390/cells13110941
APA StyleGootjes, C., Zwaginga, J. J., Roep, B. O., & Nikolic, T. (2024). Defining Human Regulatory T Cells beyond FOXP3: The Need to Combine Phenotype with Function. Cells, 13(11), 941. https://doi.org/10.3390/cells13110941