Refine regulatory T cell phenotypes and add EquivalentTo definitions for naive Treg and Tfr

[Copilot]

Adds missing EquivalentTo axioms and phenotype restrictions across several Treg-related terms to improve logical consistency and classification.

EquivalentTo axioms added

• CL_0002677 (naive regulatory T cell): CL_0000792 ∩ CL_0000898 — mirrors the memory Treg pattern using CD4+CD25+ αβ Treg as genus
• CL_0009113 (T follicular regulatory cell): CL_0000815 ∩ has_part(FOXP3) ∩ has_part(BCL6) ∩ has_plasma_membrane_part(CXCR5) ∩ has_plasma_membrane_part(PD-1) — conserved cross-species core phenotype; FOXP3/BCL6 as transcription factors use has_part, surface markers use has_plasma_membrane_part

Phenotype restrictions added

• CL_0000792 (CD4+CD25+ αβ Treg): has_part some FOXP3 — lineage-defining transcription factor (PMID:12522256, PMID:12612578)
• CL_0001045 (naive CCR4+ Treg): CD45RA+ and in_taxon Homo sapiens
• CL_0001046 (memory CCR4+ Treg): CD45RA− via lacks_plasma_membrane_part
• CL_0001047 (CD4+CD25+CCR4+ αβ Treg): in_taxon Homo sapiens

Synonyms added

• CL_0009113: "Tfr", "Tfr cell", "follicular Treg cell"

Housekeeping

• Existing SubClassOf axioms made redundant by new EquivalentTo definitions annotated with is_inferred "true"

Original prompt

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This section details on the original issue you should resolve

<issue_title>[Class hierarchy] Refine regulatory T cell phenotypes and add EquivalentTo definitions for naive Treg and Tfr</issue_title>
<issue_description>CL term
CL_0002677 — naive regulatory T cell
Suggested revision of class hierarchy
EquivalentTo:

• CD4-positive, CD25-positive, alpha-beta regulatory T cell (CL_0000792)

Rationale:
The current term lacks an EquivalentTo axiom and its lineage assignment is unclear.Because memory Treg derive from naïve Treg and use CD4-positive, CD25-positive, alpha-beta regulatory T cell as their EquivalentTo parent, assigning the same EquivalentTo parent to naïve Treg provides a consistent and biologically appropriate lineage structure.

References:
PMID:19464196

2. T follicular regulatory cell (Tfr)

CL term
CL_0009113 — T follicular regulatory cell
Suggested revision of class hierarchy
EquivalentTo:

• regulatory T cell (CL_0000815)
• FOXP3+, CXCR5+, PD-1+, BCL6+
  FOXP3 and BCL6 are transcription factors and should be attached via has part.

Synonyms:

• Tfr; Tfr cell; follicular regulatory T cell; follicular Treg cell

Rationale:
Tfr currently lacks an EquivalentTo axiom.
Because Tfr cells arise from FOXP3⁺ natural Treg rather than CD25⁺ Treg specifically (CD25 being variable across species and differentiation stages),
the most appropriate EquivalentTo parent is regulatory T cell.
Although human and mouse Tfr exhibit some differences, FOXP3 / CXCR5 / PD-1 / BCL6 represent a conserved core phenotype shared across species:

• Human Tfr: FOXP3+, CXCR5+, PD-1+, CTLA-4+, BCL6+
• Mouse Tfr: FOXP3+, CXCR5+, PD-1+, ICOS+, BCL6+
  Thus, EquivalentTo should specify the lineage only, while these core markers should be added as phenotype restrictions (Add).

References:
PMID:21785430, 21785433, 28698369

Additional proposed refinements to Treg subsets

CD4-positive, CD25-positive, alpha-beta regulatory T cell

CL_0000792
Add: FOXP3+
Rationale:
CD4⁺CD25⁺ αβ regulatory T cells represent the major natural Treg population,
and FOXP3 is the lineage-defining transcription factor essential for Treg development and suppressive function.
References:
PMID:12522256, 12612578

naive CCR4-positive regulatory T cell

CL_0001045
Add: CD45RA+, in taxon Homo sapiens
Rationale:
Human naive CCR4⁺ Treg are CD45RA⁺.(PMID:19464196)
The comment in the definition states: “The definition is valid for human; its applicability for mouse and other species is unknown.” Human naïve CCR4⁺ regulatory T cells are well-characterized in humans but have not been clearly identified or validated in mice, making a human-specific taxon assignment appropriate.

memory CCR4-positive regulatory T cell

CL_0001046
Add: CD45RA−
Rationale:
Effector/memory Treg are FOXP3^high CD45RA⁻ and correspond to the CD45RO⁺ subset defined in Miyara et al. (2009).
Reference:
PMID:19464196

CD4-positive, CD25-positive, CCR4-positive, alpha-beta regulatory T cell

CL_0001047
Add: in taxon Homo sapiens
Rationale:
The comment in the definition states: “The definition is valid for human; its applicability for mouse and other species is unknown.” Human naïve CCR4⁺ regulatory T cells are well-characterized in humans but have not been clearly identified or validated in mice, making a human-specific taxon assignment appropriate.
</issue_description>

Comments on the Issue (you are @copilot in this section)

• Fixes [Class hierarchy] Refine regulatory T cell phenotypes and add EquivalentTo definitions for naive Treg and Tfr #3461

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