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Page 4 Spiliopoulou et al. Cancer Drug Resist 2024;7:2 https://dx.doi.org/10.20517/cdr.2023.46

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Figure 2. Characterization of T cells and subsets: CD4 T cells egress from the thymus and differentiate in blood and tumor tissue.
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Depending on the degree of CD45RA and FOXP3 expression, CD4 are defined as nT cells. CD4 or nT cells egress into the
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periphery, where either cell population is subsequently altered and selected for different types of T cells. Based on the “selection
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model”, CD4 naïve cells are selected to transition into iT cells, differing in their functional status as “Tr1 cells” or Th3 cells. FOXP3:
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Forkhead box protein P3; nT : natural T regulatory cells; iT : induced T cells; Tr1 cells: type 1 T cells; Th3 cells: T helper 3 cells.
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Classification of T cells
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In general, CD4 CD25 T cells are characterized by FOXP3 [28-31] . Additionally, low expression of the IL-7
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receptor alpha chain (CD127) on the cell surface of T cells often coincides with the intracellular presence
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[32]
of FOXP3 . Therefore, some classifications use the low expression of CD127 as an alternative marker to
FOXP3, recognizing that this may not reflect the entire T cell population . Using a composite of
[33]
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intracellular and cell surface proteins, four major subsets of CD4 T cells, from which T cells are derived,
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are classified as non-T , naïve T , effector T and tumor-associated effector T cells [Table 1]. Each
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subset is further characterized by additional surface markers [31,34] .
Another nomenclature defines T cells as “fractions” [Table 1] [34,35] . This nomenclature also takes into
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consideration elements of functionality. Each T cell fraction has distinct functions depending on the type
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[36]
of organ and anatomical location within the organ [Table 1].
Some authors have preferred to define T cells based on their function. For example, “type 1 T cells”
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(Tr1) and T Helper (Th)3 cells are T cells that produce immunosuppressive factors [23,37] . In contrast to the
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tT cells, Tr1 and Th3 T secrete the immunosuppressive cytokines IL-10 and TGF-β . Others used
[38]
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HELIOS, a member of the Ikaros family of zinc-finger transcription factors, to identify precursors of
peripheral T cells emerging from the thymus and designated them as nT reg [39] . Moreover, the expression of
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neuropilin-1 is used to distinguish T cells selected from iT in peripheral or extrathymic tissues .
[29]
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Recently, the expression of programmed death 1 (PD-1) on T cells was found on a highly immune-
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suppressive subset of T cells, especially in patients previously exposed to ICI therapy . In summary, these
[40]
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observations underscore the plasticity of T cells and the selection of T cell subsets in the periphery or
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extrathymic tissues .
[41]