Blood Cells - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 134

Naive and Effector T Reg Cells

In humans, the population of CD4 , thymus-derived, naturally occurring

T cells is composed of at least 3 phenotypically and functionally distinct subpopu-
lations [ 247 ]: (1) CD45Ra

+ , FoxP3 +

, FoxP3 low

+ resting T Reg cells (rT Reg ); (2) CD45Ra − ,

FoxP3 high

activated T Reg cells (aT Reg ); and (3) cytokine-secreting CD45Ra − ,

FoxP3 low non-suppressive T cells (non-T Reg ).
Some FoxP3 + cells in peripheral blood are phenotypically naive, such as

CD45Ra + cells, whereas other FoxP3 + cells phenotypically resemble memory

T cells such as CD45Ra − cells that may originate from peripheral memory FoxP3 − ,

CD4 T cells. Expression of CD45Ra without concomitant expression of CD45Ro

is a marker for naive T cells. (The label CD45Ro is a marker of conventional
memory T cells.) CD45Ra

+

, FoxP3 low naive T Reg cells that are characterized by
plasmalemmal CD45Ra and low levels of intranuclear FoxP3 are in a quiescent
stage, hence their name, resting T Reg cells [ 244 ]. Naive T Reg cells proliferate
after TCR stimulation. They are highly resistant to apoptosis. On the other hand,
CD45Ro

+

,CD25 high , FoxP3 + + T Reg cells tend to be hyporesponsive and undergo

apoptosis, once activated.
Effector CD45Ro (PTPRc lMW ), FoxP3 high

+ T Reg cells derive mainly from

(PTPRc hMW ), FoxP3 low , resting T Reg cells. In vitro, they are potent
suppressor and hyporesponsive after activation. They express IL2R

CD45Ra +

, TNFRSF6a,
TNFRSF18, and cytotoxic T-lymphocyte-associated protein CTLA4 that are mark-
ers of recently activated T cells [ 244 ]. Effector T Reg -cell subpopulation is hetero-
geneous in the expression of ICOS and HLADR markers. Effector ICOS

α

+ and

ICOS (inducible T-cell costimulator or CD273) T Reg cells produce the suppressive

cytokines IL10 and TGF

−

, respectively. Receptor HLADR enables to identify a
terminally differentiated subpopulation of effector T Reg cells [ 244 ].

β

Role of FoxP3 Transcription Factor

Regulatory T cells that promote immune tolerance and protect against autoimmunity
develop in the thymus. Their differentiation and acquisition of suppressive function
can rely on FoxP3 expression. However, FoxP3 that is a major regulator of
T Reg cells is insufficient and unnecessary to specify all aspects of this cell lineage.
FoxP3

-T-cell antigen receptor for antigen recognition with
a TCR repertoire similar in size, but distinct in composition w.r.t. that of CD4

+ T Reg cells use the αβ

+

conventional T cells.
The transcription factor FoxP3 primes the expression of T Reg -cell markers, such
as IL2R

(CD25), cytotoxic T-lymphocyte-associated protein (antigen) CTLA4,
and TNFRSF18 (Table 3.32 )[ 244 ].
In humans, 2 main FoxP3 isoforms confer regulatory function when they
are strongly expressed. Both FoxP3a and FoxP3b possess a proline-rich region
that inhibits NFAT-mediated transcription and interacts with histone deacetylases,
zinc finger sequence, Leu zipper motif for homodimerization, and DNA-binding
forkhead domain. The 2 last domains interact with NFAT and NF

α

κ B factors [ 244 ].