Blood Cells - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 133

ceptor encoded by the human leukocyte antigen [HLA] complex) and FoxP3 [ 244 ].
Subpopulations of human FoxP3 + T Reg cells change their levels of certain markers,

, FoxP3 low naive T Reg , CD45Ra , FoxP3 high activated T Reg ,and such as CD45Ra + −

, FoxP3 low cytokine-secreting T Reg cells [ 245 ].
As for activated conventional T lymphocytes, T Reg markers of activation or
memory allow homing to locations other than the secondary lymphoid organs. In
particular,

CD45Ra −

cells
in secondary lymphoid organs and a higher percentage of T Reg cells in tissues,
such as the skin, intestinal lamina propria, and lung, binds E-cadherin [ 241 ]. The
activated, memory, CD103

α E β 7 -integrin (CD103-Itg β 7) synthesized by 20 to 30% of FoxP3 +

T Reg -cell subset can be further subdivided by markers
of natural killer cells, such as KLRg1, cyclic

+

ADP ribose hydrolase-1 (CD38), and

α 2 β 1 -integrin (CD49b-CD29).
Chemokine receptor CCR4 is not expressed on thymic T Reg cells, but on a high
percentage of extralymphoid FoxP3

+ cells in the skin. A distinct population of

FoxP3 cells that express only a subset of the T Reg signature reside in adipose

tissue [ 241 ].

+

Natural T Reg Cells

Naturally occurring, CD4 , regulatory T cells that maintain self-

tolerance originate from thymocytes. These naturally occurring (natural), thymus-
derived, T Reg lymphocytes can be detected in the periphery about 3 days after birth,
at least in mice [ 244 ].
In humans, immature FoxP3

+ ,CD25 + , FoxP3 +

thymocytes have been identified in the thymus.
The human thymus produces mature T cells from gestation week 13. From week 14,
about 7% of mature CD4

+

+ thymocytes express high levels of CD25 (IL2R α )that

,CD25 high T Reg cells [ 244 ].
In mice, thymic cortical and medullary thymic epithelial cells and dendritic cells,
contribute to T Reg -cell differentiation and selection [ 244 ]. Thymic development of
T Reg cells indeed needs interactions between their T-cell receptors and self-peptide-
MHC complexes presented by thymic stromal cells. Both IL2 and IL7 are involved
in T Reg -cell development.
In humans, Hassall's corpuscles in the thymic medulla may form a specialized
microenvironment to support nascent T Reg cells. Hassall's corpuscles release thymic
stromal lymphopoietin (TSLP) that activates immature, migratory,

produce CD4 +

α X -integrin

(CD11c) dendritic cells in the thymus and upregulates their production of cos-

timulators [ 244 ]. Dendritic cells activated by TSLP may provoke FoxP3 expression
in immature CD4

+

T
cells derived from peripheral blood, hence supporting thymocyte differentiation into
mature FFoxP3

+ ,CD8 − ,CD25 − thymocytes, but not in mature naive CD4 +

+ T Reg cells [ 244 ].