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Spiliopoulou et al. Cancer Drug Resist 2024;7:2 https://dx.doi.org/10.20517/cdr.2023.46 Page 5

Table 1. Two different classifications of T cells
reg
Classification of T cells [31]
reg
T cells subsets Phenotype Characteristics
reg
markers
-
Non T reg CD45RA No suppressive activity
+
+
CD4 CD25 FOXP3
low

+
CTLA-4 PD-1 +
+
Naïve T CD45RA Weak suppressive activity
reg + +
CD4 CD25 FOXP3 Differentiate into effector T cells
reg
low

low
CTLA-4 PD-1 -
-
Effector T CD45RA Strong suppressive activity
reg + ++
CD4 CD25 Prone to apoptosis
++
FOXP3
++ +
CTLA-4 PD-1
+
+
GITR LAG3 CD127 -
-
Tumor Effector T CD45RA High activation and proliferation
reg + ++
CD4 CD25
++
FOXP3
++
CTLA-4 +++ PD-1
++ ++
GITR LAG3
CD127 -
Classification of T cells based on the concept of “fractions (Fr)” [34,35]
reg
Fraction Classification Definition/Phenotype Characteristics
+
Fr 1 (= naïve or resting) rT CD45RA Derived from the thymus
reg + low low
CD4 CD25 FOXP3 Weak suppressive activity
low low/- -
CTLA-4 CD127 Ki67 Proliferation and differentiation into effector T by
regs
TCR stimulation
-
Fr 2 (= effector or eT CD45RA Terminal differentiation status
reg + hi hi
activated) CD4 CD25 FOXP3 Strong suppressive activity
hi + + + +
CTLA-4 , PD-1 , ICOS , GITR , OX40 , Prone to apoptosis
+
CD15s , Tend to increase in peripheral blood with aging
+ + + +
CCR4 , CCR8 , IL-10 , TGF-β
-
Fr 3 (= non-T cells) Non-T CD45RA Heterogenous population
reg reg + low low
CD4 CD25 FOXP3 No suppressive activity
+ + +
IL-2 , IFN-γ , IL-17
T cells: T regulatory cells; FOXP3: forkhead box protein P3; CTLA-4: cytotoxic T lymphocyte antigen-4; PD-1: programmed death 1; GITR:
reg
glucocorticoid-induced TNFR-related protein; LAG-3: lymphocyte-activation gene 3; TCR: T cell receptor; ICOS: inducible T-cell costimulator;
CCR: C-C chemokine receptor; IL: interleukin; TGF-β: transforming growth factor beta; IFN-γ: interferon gamma.
Molecular mechanisms generating T cells and their function [Figure 3]
reg
As highlighted above, FOXP3 is an important intracellular transcription factor determining the fate of
T cells. The myocyte enhancer factor 2D (MEF2D) is a transcription factor that influences the function of
reg
T cells [29,42,43] . The role of MEF2D is important for two reasons: first, its presence is required for the
reg
expression of IL-10, Cytotoxic T Lymphocyte Antigen-4 (CTLA-4), and inducible T-cell costimulator
(ICOS) and consequently for the acquisition of the effector T cell function. Second, MEF2D acts
reg
synergistically with FOXP3 . Such discoveries point to multiple molecular regulators to generate or
[42]
[44]
maintain T cells . Consistent with this hypothesis, recent studies have found additional master regulators
reg
of human tumor T cells . By comparing the transcriptional profile of tumor associated with matched
[45]
reg
peripheral T cells from 36 patients with four different malignancies (i.e., glioblastoma, bladder cancer,
reg
renal cell carcinoma, prostate adenocarcinoma), 17 master regulators (MRs) were identified . In vivo
[45]
CRISPR-cas9 screening with gRNA against these MRs identified Transcriptional Repressor GATA Binding
1 (TRPS-1) as an essential transcription factor for tumor-associated T cells. Genetic depletion of TRPS-1
reg
in mice delayed tumor growth by inhibiting infiltration and function of tumor-associated T cells, while
reg
preserving tolerance in the periphery.