CD4+ CD25+ CD62+ T-Regulatory Cell Subset Has Optimal Suppressive and Proliferative Potential

Abstract

CD4 + CD25 + regulatory T cells (Treg) are potent suppressors, and play important roles in autoimmunity and transplantation. Recent reports suggest that CD4 + CD25 + Treg are not a homogeneous cell population, but the differences in phenotype, function, and mechanisms among different subsets are unknown. Here, we demonstrate CD4 + CD25 + Treg cells can be divided into subsets according to cell-surface expression of CD62L. While both subsets express foxp3 and are anergic, the CD62L + population is more potent on a per cell basis, and proliferates and maintains suppressive function far better than the CD62L-population and unseparated CD4 + CD25 + Treg. The CD62L + population preferentially migrates to CCL19, MCP-1 and FTY720. Both CD62L + and CD62L-subsets prevent the development of autoimmune gastritis and colitis induced by CD4 + CD25-CD45RB high cells in severe combined immunodeficiency (SCID) mice. Overall, these results suggest CD4 + CD25 + Treg are not a homogenous cell population, but can be divided into at least two subsets according to CD62L expression. The CD62L + subset is a more potent suppressor than the CD62L-population or unfractionated CD4 + CD25 + Treg cells, can be expanded far more easily in culture, and is more responsive to chemokine-driven migration to secondary lymphoid organs. These properties may have significant implications for the clinical manipulation of the CD4 + CD25 + CD62L + cells. Tolerance is a feature of the immune system that is intimately related to discrimination between self and nonself. Clonal deletion of self-reactive T cells in the thymus is a primary tolerance mechanism, while induction of unresponsiveness or anergy in post thymic T cells may be required for the establishment of peripheral tolerance. Recent data show that Treg may play a critical role in the induction and maintenance of immune tolerance (1-5). Various types of Treg cells have been described, including Tr1 cells, Th3 cells, CD4 + CD25 + Treg cells, and others (6). CD4 + CD25 + Treg cells were first described by Sakaguchi (7). Five to 10% of CD4 + T cells constitutively expressed the a chain of IL-2-receptor (CD25) and were crucial for the control of autoreactive T cells in vivo. These cells are generated in the thymus of naïve mice, perhaps via altered negative selection by self-antigen (8). Subsequent in vitro studies showed that CD4 + CD25 + cells are typically anergic, unresponsive to TCR stimulation alone, but proliferate after addition of exogenous IL-2 (9). These cells suppress the proliferation of other CD4 + and CD8+ T cells in an antigen-nonspecific manner via a cell contact-dependent, cytokine-independent mechanism (10,11). A similar population of CD4 + CD25 + Treg cells has been defined in humans, with identical phenotypic and functional properties (12-15).CD4 + CD25 + Treg are potent suppressors in a number of in vivo models of autoimmunity, including gastritis, thyroiditis, inflammatory bowel disease and insulin-dependent diabetes (16)(17)(18)(19). Regulation of disease activity in vivo seems...

Circulating CD4+ CD25brightFOXP3+ regulatory T-cells are significantly reduced in bullous pemphigoid patients

“…CCR4 expression may drive Treg cells to sites of antigen presentation (such as the skin in BP patients) supporting the down-regulation ofT-cell activation [17]. As to CD62L expression, CD4+ CD25bright nTregs positive for L-selectin display a significantly stronger suppressor activity than the negative ones [15,29]. Taken together, the CD4+ CD25bright-FOXP3+ cells shown to be reduced in BP patients exhibited the Tregs characteristic phenotypic features.…”

Compromised lymphocytes infiltrate hepatocellular carcinoma: The role of T-regulatory cells

“…It has been suggested that the CD62L high population has greater suppressive capacity. 38 The number of isolated TILs was small, so TGF-␤1 expression was studied in only 3 patients. A proportion of CD4 ϩ CD25 ϩ cells expressed active TGF-␤1 on the membrane (35.6%, 8%-63%; n ϭ 3; see Fig.…”

Suppression of myasthenogenic responses of a T cell line by a dual altered peptide ligand by induction of CD4+CD25+regulatory cells

“…Hence, depletion of this regulatory subset induces the spontaneous onset of various autoimmune disorders (19). Several important molecules, such as glucocorticoid-induced tumor necrosis factor receptor, CTLA-4, TGF-␤, CD62L, CD45Rb low , Foxp3, and neuropilin, have emerged as markers of this unique T cell lineage (20)(21)(22)(23)(24)(25)(26). These cells act by suppressing the cytokine production and proliferation of conventional CD4 ϩ CD25 Ϫ T cells as well as that of CD8 ϩ T cells.…”